Amount of enzymes in fungal extracts.
\\n\\n
IntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
\\n\\nIntechOpen Book Series will be launching regularly to offer our authors and editors exciting opportunities to publish their research Open Access. We will begin by relaunching some of our existing Book Series in this innovative book format, and will expand in 2022 into rapidly growing research fields that are driving and advancing society.
\\n\\nLaunching 2021
\\n\\nArtificial Intelligence, ISSN 2633-1403
\\n\\nVeterinary Medicine and Science, ISSN 2632-0517
\\n\\nBiochemistry, ISSN 2632-0983
\\n\\nBiomedical Engineering, ISSN 2631-5343
\\n\\nInfectious Diseases, ISSN 2631-6188
\\n\\nPhysiology (Coming Soon)
\\n\\nDentistry (Coming Soon)
\\n\\nWe invite you to explore our IntechOpen Book Series, find the right publishing program for you and reach your desired audience in record time.
\\n\\nNote: Edited in October 2021
\\n"}]',published:!0,mainMedia:{caption:"",originalUrl:"/media/original/132"}},components:[{type:"htmlEditorComponent",content:'With the desire to make book publishing more relevant for the digital age and offer innovative Open Access publishing options, we are thrilled to announce the launch of our new publishing format: IntechOpen Book Series.
\n\nDesigned to cover fast-moving research fields in rapidly expanding areas, our Book Series feature a Topic structure allowing us to present the most relevant sub-disciplines. Book Series are headed by Series Editors, and a team of Topic Editors supported by international Editorial Board members. Topics are always open for submissions, with an Annual Volume published each calendar year.
\n\nAfter a robust peer-review process, accepted works are published quickly, thanks to Online First, ensuring research is made available to the scientific community without delay.
\n\nOur innovative Book Series format brings you:
\n\nIntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
\n\nIntechOpen Book Series will be launching regularly to offer our authors and editors exciting opportunities to publish their research Open Access. We will begin by relaunching some of our existing Book Series in this innovative book format, and will expand in 2022 into rapidly growing research fields that are driving and advancing society.
\n\nLaunching 2021
\n\nArtificial Intelligence, ISSN 2633-1403
\n\nVeterinary Medicine and Science, ISSN 2632-0517
\n\nBiochemistry, ISSN 2632-0983
\n\nBiomedical Engineering, ISSN 2631-5343
\n\nInfectious Diseases, ISSN 2631-6188
\n\nPhysiology (Coming Soon)
\n\nDentistry (Coming Soon)
\n\nWe invite you to explore our IntechOpen Book Series, find the right publishing program for you and reach your desired audience in record time.
\n\nNote: Edited in October 2021
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New trends and novel developments have been proposed to acquire and process many different biometric traits. The ignored challenges in the past and potential problems need to be thought together and deeply integrated. The key objective of the book is to keep up with the new technologies on some recent theoretical development as well as new trends of applications in biometrics. The topics covered in this book reflect well both aspects of development. They include the new development in forensic speaker recognition, 3D and thermo face recognition, finger vein recognition, contact-less biometric system, hand geometry recognition, biometric performance evaluation, multi-biometric template protection, and novel subfields in the new challenge fields. The book consists of 13 chapters. It is divided into four sections, namely, theory and method, performance evaluation, security and template protection, and other applications. The book was reviewed by editors Dr. Jucheng Yang and Dr. Shanjuan Xie. We deeply appreciate the efforts of our guest editors: Dr. Norman Poh, Dr. Loris Nanni, Dr. Dongsun Park, Dr. Sook Yoon and Ms. Congcong Xiong, as well as a number of anonymous reviewers.",isbn:null,printIsbn:"978-953-51-0859-7",pdfIsbn:"978-953-51-5716-8",doi:"10.5772/3420",price:139,priceEur:155,priceUsd:179,slug:"new-trends-and-developments-in-biometrics",numberOfPages:344,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"beef3079663a77be4c578d4454065e7d",bookSignature:"Jucheng Yang, Shan Juan Xie",publishedDate:"November 28th 2012",coverURL:"https://cdn.intechopen.com/books/images_new/3120.jpg",numberOfDownloads:41953,numberOfWosCitations:65,numberOfCrossrefCitations:58,numberOfCrossrefCitationsByBook:9,numberOfDimensionsCitations:85,numberOfDimensionsCitationsByBook:10,hasAltmetrics:1,numberOfTotalCitations:208,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 14th 2012",dateEndSecondStepPublish:"March 6th 2012",dateEndThirdStepPublish:"June 2nd 2012",dateEndFourthStepPublish:"July 2nd 2012",dateEndFifthStepPublish:"October 1st 2012",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"36689",title:"Dr.",name:"Jucheng",middleName:null,surname:"Yang",slug:"jucheng-yang",fullName:"Jucheng Yang",profilePictureURL:"https://mts.intechopen.com/storage/users/36689/images/1760_n.jpg",biography:"Jucheng Yang is a special professor of Haihe Scholar in College of Computer Science and Information Engineering, Tianjin University of Science and Technology, Tianjin, China. He is a special professor of Tianjin City, too. He received his B.S. degree from South-Central University for Nationalities, China, and M.S. and Ph.D. degree from Chonbuk National University, Republic of Korea. He did his post-doc at the Advanced Graduate Education Center of Jeonbuk for Electronics and Information Technology-BK21 (AGECJEIT-BK21), Republic of Korea. He was a professor in Jiangxi University of Finance and Economics, China and was a visiting fellow in the University of New South Wales, Australia. He has published over 50 papers in related international journals and conferences. He has served as editors or reviews of international journals such as IEEE Transactions on Information Forensics & Security, Sensors, Science China, Information Technology Journal and so on, and as reviewers or PC members of many conferences such as ICNC\\'06-FSKD\\'06, IMPRESS’09, FIRM-EPECC’11. He is the publicity chair of ICMeCG’10-11. 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Its incidence and prevalence are increasing worldwide. Extensive research has completely changed the landscape of the biology, pathophysiology, and treatment of thyroid cancer. It has become evident that some forms of thyroid cancer have a benign biologic behavior, while others have a more malignant one. For progressive thyroid cancer, multiple growth factors and kinase inhibitors may be beneficial. Treatment of thyroid cancer with radioiodine has been also completely revised. For the reader, it is important to know everything about the incidence and prevalence of thyroid cancer. It is also important to know the result of in-depth research on the biology and pathophysiology of thyroid cancer. It is also important to recognize factors relevant to the benign biologic behavior of the disease. The advent of multiple growth factors and kinase inhibitors has revolutionized the management of the disease. The indications and adverse effects of these agents are important to know. The long-term prognosis of the disease is also an important subject and will be addressed in this book.
",isbn:"978-1-80356-285-8",printIsbn:"978-1-80356-284-1",pdfIsbn:"978-1-80356-286-5",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,isNomenclature:!1,hash:"b74aed61ed1639fc9ad70c20d591a10c",bookSignature:"Dr. Ifigenia Kostoglou-Athanassiou",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11652.jpg",keywords:"Genes, Mutations, Thyroidectomy, Lymph Nodes, Resection, Treatment, Multikinase Inhibitors, Growth Factor Inhibitors, Molecular Targeted Treatment, Radioiodine Treatment, Side Effects, Prognostic Factors",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 11th 2022",dateEndSecondStepPublish:"April 15th 2022",dateEndThirdStepPublish:"June 14th 2022",dateEndFourthStepPublish:"September 2nd 2022",dateEndFifthStepPublish:"November 1st 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"4 months",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"An active clinical endocrinologist, head of the endocrine department of the Asclepeion Hospital, Athens, awarded her Ph.D. from the Univerisity of London. 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In agricultural soils, approximately 29–34 million kg of atrazine are applied per year [1]. In Mexico, more than 45% of pesticides are categorized as herbicides, and atrazine is one of the most commonly used herbicides in Mexican agriculture [2]. Since 1975, atrazine has been applied to control broadleaf and grass weeds in agricultural crops, including corn, sorghum and sugar cane. Atrazine kills susceptible plants by binding to the quinone protein in photosystem II and inhibiting photosynthetic electron transport [3].
\nAtrazine is a pre-emergent herbicide and is considered to have low persistence in soil (<12 months). However, its low mobility in soil and its physical and chemical properties contribute towards the contamination of ground and surface waters, which represents a risk to the environment and to human health [4]. In Mexico, atrazine levels in water often exceed the maximum permissible levels for drinking water (0.1 μg L−1) as established by Europe and by the health advisory board of the United States Environmental Protection Agency (EPA) [5, 6]. At a molecular level, atrazine has distinct fates in the environment and may be found in soil, water, biomass (plants) or air. In soil, atrazine is adsorbed by clay particles; however, other adsorption-desorption processes may be involved in its translocation in plants, movement in soil and mobility in aqueous systems, as well as its eventual abiotic or biological degradation [7].
\nThe clean-up of soils contaminated with atrazine is an ecological responsibility, and the discovery of a safe and economical method is a major priority for land management agencies [8]. One such possibility is mycoremediation, or the use of fungal organisms and their enzymes to degrade or transform environmental pollutants [9]. This strategy has been used to degrade pesticides [10], aromatic and polycyclic hydrocarbons [11] and endocrine disruptors [12]. The degradation of environmental pollutants by fungi, specifically by white-rot fungi, is due to their ability to synthesize ligninolytic enzymes, such as laccase, manganese peroxidase and lignin peroxidase, as well as their production of hydrogen peroxide [13, 14].
\nHowever, mycoremediation faces several challenges in order to improve the feasibility of this strategy. The following issues, for example, should be addressed: (i) the competition/proliferation of native soil microorganisms (actinomycetes and bacteria) may inhibit the growth of bioremedial fungi; (ii) bioremedial fungi have a limited capacity to produce ligninolytic enzymes. Enzyme production varies depending on the strain and species and is mainly influenced by the content and availability of nutrients (carbon, nitrogen, metal ions, etc.), which stimulate fungal growth and the synthesis of ligninolytic enzymes; finally, (iii) edaphic and environmental factors may adversely affect the establishment and growth of bioremedial fungi [9].
\nThe use of fungal extracts with a proven high activity of ligninolytic enzymes is one means of improving the degradation of pollutants in soil, which may also address some of the aforementioned challenges. Ligninolytic enzymes in white-rot fungi, for example, may be enhanced through the use of fungal co-cultures, although the mechanism by which increased enzyme activity occurs has not yet been described [15]. Given this context, the objectives of the study were: (i) to evaluate the degradation of atrazine in soil microcosms by a white-rot fungus (
The white-rot fungi
The soil-borne micromycete
Soil samples were collected from the first horizon of <20 cm profundity at a sugar cane plantation in Mahuixtlan, Veracruz, Mexico (location: 19°23′21.3″ N, 96°53′34.9″ W). Plant residues and rocks were removed manually. Soil was sieved in 2 mm mesh in the laboratory and dried at 20°C for 5 days prior to use. The physical and chemical characteristics of the soil were determined using standard methods to establish texture (clay loam soil), soil organic matter (4.35%), pH (4.86), NH4-N (5.8 mg kg−1), soluble salts (5.38 S m−1), acidity (0.053 meq 100 g−1), cation exchange capacity (16.41 meq 100 g−1), water holding capacity (WHC) (53.6%) and electrical conductivity (53.75 μS cm−1).
\nModified Sivakumar culture medium [16] was used to produce laccase, MnP and H2O2 for the monoculture of
Laccase activity was determined according to More et al. [17] by measuring the oxidation of ABTS [2,2′-azino-bis (3-ethylbenzthiazoline-6-sulfonic acid)] in a reaction mixture (1 mL) containing 100 μL of ABTS (0.5 mM, Sigma, St. Louis, MO, USA), 800 μL of acetate buffer (100 mM, pH 4.5) and 100 μL of enzyme extract. Absorbance changes in the presence of the enzyme were monitored during 5 min at 420 nm (
MnP activity was determined at 610 nm (
H2O2 content of the fungal enzyme extracts (FEEs) was determined using the iodide/iodate method, according to Klassen et al. [19]. Three milliliters of the FEEs were mixed with 3 mL of a solution containing KI (33 g), NaOH (1 g) and (NH4)6Mo7O24 × 4H2O (0.1 g) in 500 mL of distilled, deionized water, in addition to 3 mL of a solution containing C8H4KO4 (10 g) in 500 mL of distilled, deionized water. The absorbance of the resulting solution was measured at 351 nm in a 3 cm3 cuvette. The blank absorbance was determined by substituting the FEEs with a sterile Sivakumar culture medium in the reaction mixture. Hydrogen peroxide content was calculated by substituting with H2O2 reagent (30%, J.T. Baker™) according to the standard curve of the absorbance of known concentrations (0.0, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0 and 3.5 mg L−1).
\nBiodegradation of atrazine was evaluated in sterile soil microcosm conditions. First, 20 g of air dried soil was placed in serological flasks (100 cm3). Then, the sterile soil was contaminated with atrazine (Sigma-Aldrich Co., USA) at the field application rate of 5mg/kg [8], and 20 mL of methanol were added (analytical grade, Honeywell Burdick & Jackson, Muskegon, MI, USA). Soil-methanol-atrazine was mixed using a sterile spatula until the complete evaporation of methanol under a laminar flow hood.
\nThree treatments were evaluated:
Experiments were conducted using six sorbate concentrations of atrazine (0.5, 1, 5, 10, 20 and 30 mg/kg). Two grams of all soil samples were added to a polypropylene bottle (20 mL), and immediately 5 mL of a methanol solution with the sufficient amount of atrazine was added to obtain the established concentration. Bottles were shaken vigorously (24 h) and placed on a flat rotator shaker (120 rpm) at room temperature (27 ± 1°C) [20]. Four replicates were used for each initial concentration of atrazine. After an equilibration period (24 h), samples were centrifuged in cold (5°C) at 7000 rpm during 20 min. Then, 0.2 mL of supernatant was filtered through a 0.22 μm nylon syringe. The filtrate was used to analyze the atrazine adsorbed using HPLC.
\nDesorbed atrazine was determined by examining the solid phase of the centrifuged samples; 5 mL of methanol was added in each bottle and shaken during 24 h at 120 rpm in a flat rotatory shaker. After the agitation period, the bottles were centrifuged and filtered as mentioned above for further atrazine analysis.
\nThe analysis of atrazine degradation and its desorption-adsorption was performed using a Thermo-Scientific HPLC system coupled to a diode array detector (SpectraSystem UV8000), a sampling injector (SpectraSystem AS3000) and a pump (SpectraSystem P4000) equipped with a Restek ultra C18 column (5 mm × 150 mm × 4.6 mm). The column was operated at 25°C with a flow rate of 1.0 mL min−1 and an injection volume of 20 μL. An isocratic mobile phase was established using acetonitrile-water at a ratio of 70:30. The HPLC-photodiode array detector was monitored at 215 nm [8]. The HPLC method had a running time of 10 min and a retention time of 3.8 min, which enabled the detection and quantification of atrazine. The atrazine detection limit was 0.05 mg g soil−1. The standard curve for atrazine [atrazine = (peak area – 491818)/804962] was made using a standard analytical solution (Sigma-Aldrich Co., USA) at different concentrations, and the
Laccase activity and H2O2 production in the fungal co-culture (laccase = 18956.0 U/mg of protein and H2O2 = 6.2 mg/L) were significantly higher (
Fungal enzyme extracts | \n||||
---|---|---|---|---|
Variable | \nCo-culture | \nMean Comparison test | \n||
Laccase (U/mg of protein) | \nND | \n12866.2 ± 446.7 | \n18956.0 ± 204.0 | \n[ | \n
MnP (U/mg of protein) | \nND | \n572.4 ± 31.8 | \n542.6 ± 43.5 | \n\n [ | \n
H2O2 (mg/L) | \n0.9 ± 0.07 c | \n4.2 ± 0.10 b | \n6.2 ± 0.15 a | \nFisher [ | \n
Amount of enzymes in fungal extracts.
Laccase and MnP were compared with the
Laccase is an important enzyme in white-rot fungi; this enzyme is a defence mechanism against saprotrophic and parasitic microfungi. This phenomenon has been reported for
One of the principal applications of fungal co-cultures is to increase ligninolytic enzyme activity (laccase, MnP and LiP), and these may then be applied to resolve environmental problems, such as the contamination of soil and water with pesticides or the presence of endocrine disruptors, medical drugs, hydrocarbons, dyes or other emerging contaminants in the environment. Several studies have reported that soil-borne micromycetes enhance ligninolytic enzyme activity in white-rot fungi; for example, Baldrian [25] reported that
\nFigure 1 shows atrazine degradation by fungal enzyme extracts (FEEs) from the monocultures of
Atrazine degradation at 1 h (A), 3 h (B), 6 h (C) and 12 h (D) after application of fungal enzyme extracts in a clay-loam soil. Bars (mean ± standard error) with different letters are statistically different from one another (LSD test
At 6 h after application (Figure 1C), the relationship of
However, during evaluation the degradation of atrazine by the fungal co-culture enzyme extract increased once again (92.2% at 12 h). This may be due to a desorption effect of atrazine previously absorbed by soil particles, principally clay. Meanwhile, the
During mycoremediation, a single strain is commonly used. The application of bioremedial fungi in the soil is often based on the inoculation of immobilized mycelium in organic substrates, such as pine sawdust, wood chips, peat, corn cobs, wheat straw, bark, rice grains, sugarcane bagasse, coffee pulp or sugar beet pulp [27–30]. However, this technology has several challenges to overcome, which are as follows: (i) the competition and proliferation of native soil microorganisms (microfungi, bacteria and actinomycetes) with bioremedial fungi [9]; (ii) the limited capacity of inoculated fungi in the soil to produce sufficient amounts of the ligninolytic enzymes responsible for degrading contaminants [31–33]; (iii) the adverse effects of environmental and edaphic conditions on the establishment or growth of bioremedial fungus [14] and (iv) the amount of contaminants in the soil, which in some cases may be toxic to the bioremedial fungi [14].
\nOne alternative for overcoming these challenges is the use of fungal enzyme extracts produced in fungal co-culture systems, which may enhance the amount of ligninolytic enzymes [34]; these extracts may then be applied to soil through irrigation systems by drenching or by immobilizing ligninolytic enzymes in chitosan, alginate or nanoparticles [35]. In our study, we applied fungal enzyme extracts from a co-culture to degrade atrazine in a clay-loam soil and found efficiencies of 100% at 6 and 12 h. Other studies have reported the ability of white-rot fungi extracts to degrade atrazine. For example,
Several additional studies have used fungal co-cultures or their products, such as ligninolytic enzymes, to degrade contaminants. Recently, Pan et al. [37] demonstrated the feasibility of the fungal co-culture extract between
\nFigure 2 shows the adsorption-desorption of atrazine in the studied clay-loam soil. Depending on the concentration of atrazine dissolved in soil, between 39% and 77% is absorbed (Figure 2A). More atrazine is adsorbed than desorbed, or in other words, the desorption of atrazine is slower than its adsorption given the studied the soil type and time period (24 h, Figure 2B). Atrazine desorption is slower when high concentrations are adsorbed by the soil; i.e., when 20 mg/L was absorbed, only 1% was desorbed at 24 h. In this sense, Davidchik et al. [39] suggest that the adsorption of atrazine may be irreversible if a high concentration is found in the soil; these authors consider that oxidative binding is the most probable mechanism of atrazine incorporation into the organic matter.
\nAdsorption (A) and desorption (B) of atrazine in a clay loam soil.
Adsorption and desorption values were linearized using the Freundlich equation (Eq. (1)), where
Linearized Freundlich isotherms for atrazine adsorption (A) and desorption (B) from a clay-loam soil.
Soil | \nAdsorption | \nDesorption | \n|||||||
---|---|---|---|---|---|---|---|---|---|
\n | \n\n | \n\n | \n\n | \n\n | \n\n | \n\n | \n\n | \nH | \n|
Clay-loam | \n8.2148 | \n0.8230 | \n0.992 | \n0.0001 | \n5.4992 | \n1.436 | \n0.245 | \n0.036 | \n0.573 | \n
Freundlich isotherm parameters and hysteresis index values for atrazine adsorption-desorption in a clay loam soil.
\n
The Freundlich constant for adsorption of atrazine was 8.2148, which was higher than that reported by Kulikova et al. [7], who studied the absorption of atrazine to three soils with different textures (silt-loam: sod-podzolic [
On the other hand, the Freundlich desorption constant for atrazine was lower (
We conclude that:\n
The co-culture of
Both the fungal enzyme extract of the monoculture of
Atrazine was highly adsorbed by the studied clay-loam soil. This was reflected by its high Freundlich coefficient for adsorption and low coefficient for desorption.
We thank Dra. Gabriela Heredia Abarca for donating the
Hematopoiesis is a highly controlled process that ensures the differentiation of the hematopoietic stem cells (HSCs) into lymphoid and myeloid common progenitors and further into all lineages of blood cells [1].
Programmed cell death (PCD) is one of the fundamental mechanisms of an organism’s life cycle that controls every system, including hematopoietic system, based on a precisely tuned signaling network. Apoptosis, the most important type of PCD, maybe because it is the most analyzed type of death to date, is well described in hematopoietic differentiation [2]. Its deregulation in pathological circumstances is potentially deleterious and may influence the fate of the entire organism. Although different other types of PCD were described, apoptosis remains one of the most important processes involved in differentiation and cell survival regulation, while mechanisms as autophagy and necroptosis look like “backup” mechanisms that share some “key players” and diverged from apoptosis at a certain point, to assure the elimination of the malfunctioning system in case of “internal” defect (mutations) or pathogens that inhibit the components of the apoptotic network [3, 4].
Primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocythemia (ET) are classic BCR-ABL1-negative myeloproliferative neoplasms (MPNs) that are stem cell-derived clonal disorders characterized by hematopoietic progenitor autonomy or hypersensitivity to cytokines, driven by acquired somatic mutations in critical pathways, resulting in pathological expansion of the myeloid lineages. In their natural course, MPNs could be exacerbated and transformed into secondary acute myeloid leukemia (sAML) associated with treatment resistance and poor clinical outcome [5].
This chapter will explore the most important modifications affecting programmed cell death pathways involved in myeloid proliferation, and how these alterations might be exploited in single or combined targeted therapeutic strategies in a classic BCR-ABL1-negative MPN.
Overall, the hematopoietic homeostasis requires a precise balance between blood cell formation and maintenance of an adequate number of mature cells. Although apoptosis is necessary to prevent the excessive accumulation of cells, the hematopoietic progenitors need to be protected and preserved. A disruption of the homeostatic balance in the hematopoietic system is relevant for many hematological disorders, an increased cell death being involved in the etiology of immune deficiencies and anemia, while an inappropriate resistance to apoptosis might lead to hematological malignancies [6], such as MPNs.
As a particular form of PCD, apoptosis is activated via two convergent pathways: the intrinsic and the extrinsic [7]. The intrinsic signaling pathway is triggered at mitochondrial level in response to various stimuli such as genotoxic agents or growth factor deprivation, and it is mainly regulated by the members of BCL-2 protein family that contain one or more BCL2 homology (BH) domains [8]. These proteins are structurally and functionally classified into three groups. The first group includes the critical effectors of the intrinsic pathway, namely BCL-2 antagonist killer 1 (BAK) and BCL-2-associated X protein (BAX). The second group is represented by the prosurvival BCL-2 proteins (BCL-2, BCL-xL, MCL-1, BCL-W, and A1) that hinder BAK and BAX activation, while the third group comprises several structurally different proteins, known as “BH3-only” proteins (BIM, BID, BAD, BIK, PUMA, and NOXA), which share solely a sequence called BH3-domain [8, 9]. Cellular stress signals are sensed by the “BH3-only” proteins that directly activate BAK and BAX or neutralize the prosurvival proteins. Once activated, through conformational changes, BAK and BAX induce the permeabilization of the mitochondrial membrane with subsequent release of apoptogenic factors, such as cytochrome c and second mitochondrial activator of caspases/direct IAP binding protein with low pI (SMAC/DIABLO). Cytochrome c binds to the apoptotic protease activating factor-1 (APAF-1) and forms the apoptosome, a heptameric complex that activates the initiator caspase-9, followed by activation of the effector caspase-3, caspase-6, and caspase-7 that trigger final events of apoptosis [10, 11].
In the extrinsic apoptotic pathway, caspase activation is elicited at the level of “death receptors” (DR), transmembrane proteins of the tumor necrosis factor (TNF) receptor superfamily typically represented by FAS (CD95), TNF receptors, and TNF-related, apoptosis-inducing ligand (TRAIL) receptors. Through interaction with their corresponding ligands—FASL, TNF-α, and TRAIL, respectively—DR become activated, leading to the recruitment of a death adaptor protein, such as FAS-associated death domain (FADD) or TNFR-1-associated death domain (TRADD). Death adaptors generate a death-inducing signaling complex (DISC), in which procaspase-8 is recruited and activated, the death signal being subsequently transduced to the effector caspases [2, 10].
A very early apoptosis event is the global and rapid mRNA degradation by a mechanism that is not yet completely characterized [12].
Various factors associated with intrinsic and extrinsic apoptotic pathways have been involved in the control of adult hematopoiesis under physiological as well as pathological conditions [2]. In this respect, BCL-2 protein family members play different roles across individual hematopoietic lineages during differentiation and maturation. At the level of HSCs and early myeloid progenitors, MCL-1 is an essential prosurvival factor, being upregulated by stem cell factor and interleukin-3 via JAK/STAT (Janus-activated kinase/signal transducers and activators of transcription) and AKT signaling pathways [13, 14]. During erythropoiesis, erythropoietin (EPO) ensures erythroid progenitor survival, proliferation, and differentiation by acting on its cognate receptor (EPO-R) and inducing JAK2-STAT5 activation that leads to upregulation of BCL-xL [10]. The development, maturation, and survival of megakaryocytes (MKC) is strictly dependent on the presence of both BCL-xL and MCL-1 proteins that are induced by thrombopoietin (TPO) signaling and restrain intrinsic apoptosis, while platelet life span seems to be dictated only by BCL-xL levels [7, 15, 16]. Similarly, MCL-1 is essential for granulocyte progenitor survival and differentiation [16]. On the other hand, the receptor/ligand interactions of the TNF family represent physiological mechanisms that exert a negative regulation in the terminal stages of the hematopoietic differentiation, controlling in this way the size of the expanding hematopoietic clones and maintaining heterogeneity in response to various demands [17].
PV is characterized by erythrocytosis accompanied by a suppressed endogenous EPO production. It often associates thrombocytosis and/or leukocytosis with panmyelosis at bone marrow examination. The pattern of driver mutations is strikingly dominated by
A study that analyzed gene expression profile of granulocytes isolated from PV patients showed an upregulation of protease inhibitors with affinity for proteases inducing apoptosis in neutrophils (e.g., cystatin F and secretory leukocyte protease inhibitor), as well as of several antiapoptotic and survival factors (e.g., p38 MAPK), compared to granulocytes obtained from healthy subjects [19]. Also, unlike the granulocytes of ET patients or normal controls, the granulocytes of PV patients were found to express an increased amount of heat shock protein 70 (HSP70), which counteracts apoptosis at different levels by preventing BAX translocation to mitochondria, inhibiting APAF-1 and procaspase-9 recruitment to apoptosome, and reducing caspase activation. As shown in primary cell cultures, an HSP-70 inhibitor was able to induce apoptosis in the erythroid lineage [20].
Concerning the extrinsic apoptosis pathway, it was found that erythroblasts isolated from PV patients carrying
ET is defined by thrombocytosis associated with normocellular bone marrow and hyperplasia of enlarged MKC. The molecular profile of ET consists of
Before the discovery of
In a study that aimed to characterize the immunophenotypic apoptotic profiles of MKC on bone marrow biopsy samples obtained from MPN patients, it was observed that ET MKC displayed an antiapoptotic pattern, characterized by an overexpression of BCL-xL and a lower expression of BAX, compared to those of PMF patients [24]. Furthermore, Treliński et al. confirmed by flow cytometry the antiapoptotic profile of ET MKC and bone marrow mononuclear cells (BMMC). As opposed to controls, previously untreated ET patients presented significantly lower percentages of apoptotic MKC and BMMCs, when assessed for the number of annexin-V+ and caspase-3+ positive cells. These findings were accompanied by markedly lower BAX levels and BAX/BCL-2 ratios, especially in
Compared to PV and ET, PMF is a more heterogeneous disease, being characterized by clonal myeloproliferation, abnormal cytokine expression, early bone marrow fibrosis, anemia, splenomegaly, extramedullary hematopoiesis, constitutional symptoms, and a lower overall survival rate. On the other hand, during the natural course of the disease PV and ET patients might suffer a conversion into secondary myelofibrosis (MF) that resembles PMF [26, 27]. PMF shares with ET a similar profile of mutations in
Initially, it was suggested that bone marrow MKC in PMF might undergo an increased apoptosis that could be responsible for the release of fibrogenic cytokines [28]. However, further studies have demonstrated that PMF MKC displayed a high proliferative capacity and resistance to apoptosis, explained by the overexpression of BCL-xL [29]. Also, the gene expression analysis of laser-microdissected MKC from PMF patients indicated a tendency toward an overall downregulation of apoptosis-associated genes, especially of
Chronic inflammation sustained by the continuous release of proinflammatory cytokines and chemokines and subsequent bone marrow microenvironment alterations are considered key factors in PMF pathogenesis. The abnormal production of cytokines that occurs both in malignant and nonmalignant cells was related to an increased JAK2-STAT3 activation and was found responsible for the inhibition of apoptosis and increased myeloproliferation, creating an environment that favors MPN clone maintenance and expansion [31, 32]. Recently, it was shown that MF cells downregulated the expression of X-linked inhibitor of apoptosis (XIAP) and mitogen-activated protein kinase 8 (MAPK 8), a necessary component of TNF-mediated apoptosis, via a TNF/TNFR2-dependent autocrine loop. This was considered a mechanism to escape an apoptotic response and to increase NF-κB signaling involved in inflammatory cytokine expression [33].
Overall, these data show the importance of the participation of both intrinsic and extrinsic apoptosis pathways in the pathogenesis of MPNs.
Modifications occurred in the regulation of apoptosis, especially in expression of pro- and antiapoptotic genes, have great contribution to the myeloaccumulation in MPNs. Concerning the involvement of other types of PCD in myeloproliferations, few data are available. Some key players are involved in apoptosis regulation and also in autophagy or necroptosis. More often, it is a continuous process from apoptosis, autophagy to necroptosis. Increased death signals and stress levels can switch cell death types in the attempt of eliminating the malfunctioning cells [34, 35].
BCL-2 family of proteins is a very important regulator of apoptosis and, at the same time, is also a negative regulator of BECN1/Beclin-1, a key regulator of autophagy [36, 37]. Autophagy was shown to be a major contributor to chemotherapy resistance in AML [38].
BCL-xL promotes cell survival, such as survival of erythroid cells and platelets, and regulates their lifespan at a steady state. Inhibition of BCL-xL induces profound thrombocytopenia by triggered BAK/BAX-mediated mitochondrial damage, caspase activation, and premature death of MKC [39, 40]. In MPNs, a concerted effect resulted from antiapoptotic BCL-xL over-expression and proapoptotic BNIP-3 downregulation was clearly documented [41].
Bcl-2-associated death promoter (BAD) inhibits antiapoptotic proteins BCL-2 and BCL-xL and is involved in initiating the apoptosis process. In unphosphorylated form, BAD forms heterodimers with BCL-2 and BCL-xL, inhibiting their antiapoptotic functions, and facilitates BAX/BAK activation in response to apoptotic stimuli [42, 43], promoting apoptosis. After activation by phosphorylation, BAD forms a heterodimer with 14-3-3 proteins, releasing BCL-2 that is free to block apoptosis. BAD is a substrate of various kinases, such as AKT, protein kinase A (PKA), and c-Jun NH2-terminal kinase (JNK).
Gene expression studies on CD34+ cells and peripheral leukocytes isolated from ET and PMF patients indicated that mRNA levels of
Studies focused on the apoptosis deregulation in PV identified an increased expression of
Survivin is one of the inhibitors of apoptosis proteins (IAPs) that regulate cell death through mitochondrial route by restricting the IAP-inhibitor DIABLO protein and preventing it from activating caspase-9. A greater proportion of myeloproliferative MKC express survivin compared to its reciprocal inhibitor, DIABLO. Survivin seems to be the key mediator of the MKC survival signature in the MPNs and might be a potential therapeutic target [41]. Recently, new evidence suggested that survivin may be involved in the evasion of cell death by manipulation of autophagy [49].
BNIP-3 (BCL2/adenovirus E1B 19 kDa protein-interacting protein 3), a proapoptotic mitochondrial protein belonging to the BCL-2 family, is activated under hypoxic conditions with hypoxia-inducible factor (HIF-1α) in normal and cancer tissues. BNIP-3 is involved in the induction of hypoxic necrosis in tumors because it activates caspase-independent necrosis-like cell death by opening the mitochondrial permeability transition pore. In MPNs, BNIP-3 expression is reportedly low and this might indicate that the increased bone marrow cellularity is not only because of proliferative signaling but also due to decreased apoptosis [50, 51].
CALR is a multifunctional endoplasmic reticulum (ER) chaperone involved in the quality control of N-glycosylated proteins, calcium storage, and immune responses [27, 52]. In relation to apoptosis, CALR is implicated in the specific activation of caspase-8, BAX, and BAK, and also in the BCL-2 cleavage [53].
Caspase-8, a key factor in the extrinsic pathway, together with caspase-9, a key factor in the intrinsic pathway, is implicated in regulating MKC turnover [41].
Immunohistochemistry studies showed that the percentage of MKC positive for caspase-8 is higher in MPNs in comparison with controls, suggesting that MKC in MPN tend to counteract the survival advantages acquired through inhibition of the intrinsic apoptotic pathway by activating the caspase-8-mediated extrinsic apoptotic cascade[41].
Caspase-9 is an inducible proapoptotic molecule, which acts relatively late in apoptosis signaling becoming less susceptible to inhibition by apoptosis inhibitors [56]. Caspase-9 is an apoptotic initiator caspase in MKC and platelets being necessary for their efficient death, and it is not required for platelet generation and function, as it was previously thought. Thus, caspase-9 loss is associated with an increased MKC proliferative capacity. In MPNs, especially in the
SMAC/DIABLO controls apoptosis by negatively regulating IAPs and by activating caspases. Recently, it was shown that silencing of SMAC/DIABLO caused decreased levels of phospholipids, suggesting that besides proapoptotic functions, SMAC/DIABLO have nonapoptotic lipid synthesis-related function essential for cancer growth and development. Therefore, it was assumed that SMAC/DIABLO could be a promising therapeutic target in cancer [57]. On the other hand, SMAC/DIABLO downregulation was found to be associated with progressive disease and poor survival rate in hematologic malignancies, and DIABLO/SMAC mimetics were proposed as a potential adjunct therapy to enhance DIABLO levels in MPN MKC [41]. More studies are necessary to establish the proper therapeutic options in the light of the new role of SMAC/DIABLO in the phospholipid synthesis.
The tumor suppressor gene
Cell surface death receptor-ligand interaction, such as FASL binding FAS, TRAIL binding death receptor 5 (DR5) or TNFα binding TNFR1, executes extrinsic pathway apoptosis.
The two major necroptotic death effector complexes, the necrosome and ripoptosome, are induced by TNFR1 and toll like receptor 3 (TLR3) signaling, respectively [60]. IFN-R activation, primarily by type-I IFN, is believed to involve a caspase- and FADD-independent, receptor-interacting protein kinase (RIP) 3-dependent mode of cell death via the formation of the necrosome. Following IFN-R activation, JAK/STAT signaling and the activity of RNA-responsive protein kinase (PKR), upstream of RIP1/RIP3 necrosome formation is essential. TNFα binding to TNFR1 causes recruitment of TRADD and RIP1 via their death domains resulting in the prosurvival complex I, which is stabilized by TNFα-bound TNFR2-TRAF2. Internalization of the TNFR1-TRADD-RIP1 complex is required for recruitment of caspase-8 and FADD, necessary for apoptosis. This is therefore a major cell death checkpoint as the absence of NF-κB activation and prosurvival signaling results in proapoptotic complexes or, alternatively, the pronecroptotic complex known as the necrosome. The ripoptosome consists of FADD, cFLIP and caspase-8 and allows necroptosis to prevail if active cleavage of RIP1 by caspase-8 is prevented by cFLIPL. In MPN, it was shown that blocking TNFR2 but not TNFR1 selectively inhibits MPN cells over normal ones and the process involves XIAP, cIAP, and MAPK8 as key mediators of these differential responses to TNF. These data support the potential therapeutic use of cIAP inhibitors and selective TNFR2 inhibitors in the treatment of MF [33].
The TLR3-induced pathway converges with the TNFR1-induced pathway at the necrosome. The execution phase of necroptosis starts with interaction between RIP1 and RIP3. Following stabilization of the RIP1-RIP3 complex, mixed-lineage kinase domain-like protein (MLKL) is recruited to form a functional necrosome. MLKL activated upon phosphorylation by RIP3 results in the translocation of the MLKL necrosome to the plasma membrane, necroptotic membrane disruption, and release of liposomes containing phosphatidylinositol phosphates (PIPs). This permeabilization, combined with MLKL-mediated calcium or sodium influx ion-pore dysregulation, characterizes the model proposed for necroptosis execution [60]. Human cancers, including MPN and their exacerbated form, sAML, are known for eluding apoptosis; therefore, therapeutic induction of necroptosis may represent a better strategy for an efficient treatment. A series of compounds have been shown to trigger necroptosis, particularly inhibitors of RIP1, RIP3 or MLKL, in leukemia cells; however, a deeper understanding of the signaling network that regulates this type of PCD is still necessary [35].
The constitutive activation of JAK-STAT pathway is a common feature of MPNs irrespective of driving mutation, being observed even in so-called “triple-negative MPNs” that lack known
Major signaling pathways involved in apoptotic failure in molecular subgroups of MPN.
In addition, loss-of-function or neomorph mutations in genes that are involved in epigenetic regulation, splicing, and signaling can act as disease modifiers by cooperating with MPN driver mutations [52].
The JAK/STAT is the major pathway (Figure 1a) involved in MPN pathology [64, 65, 66].
The MAPK/ERK signaling pathway activation (Figure 1b) is required in MKC differentiation, with TPO as signal for induced maturation via MPL receptor [71].
An increased activation of RAS/RAF/ERK pathway was showed in MPN patients, especially in erythroid precursor cells and MKC (Figure 1b). It was shown that ERK is constitutively activated by the
The PI3K/AKT signaling pathway (Figure 1c) may be activated by the
The activation of AKT upregulates BCL-xL and inactivates BAD, suppressing apoptosis and promoting cell survival. This was observed in MPN patients, where the activation of pAKT was higher in MKC and associated with the inhibition of MKC apoptosis [50]. pAKT is also known to induce activation of BNIP-3 and caspase-9 through mammalian target of rapamycin (mTOR)—a serine/threonine kinase that is an effector protein of AKT—via activation of HIF-1. Data related to BNIP-3 expression are conflicting; some groups reported a reduced BNIP-3 expression [30], whereas others have shown its upregulation in MPNs [50]. In the study of Koopmans et al., the immunohistochemical expression of BNIP-3, with proapoptotic function, was lower in total bone marrow cells of ET, PV, and PMF patients, compared with the control group. This suggests that a decreased apoptosis might also contribute to the increased bone marrow cellularity observed in MPNs. However, in contrast to total bone marrow cells, the MKC of MPN patients were found to display a high level of BNIP-3 [50]. On the other hand, the most pronounced reductions in BNIP-3 were observed in PMF, suggesting a loss of proapoptotic potential during progression to the “accelerated” phase of MPNs [80].
Noncanonical
Taking into account the above-mentioned cellular and molecular effects of MPN driver mutations, we can assume that megakaryocytic and erythroid progenitor expansion in MPNs results from a combination of increased proliferation and attenuated apoptosis.
As shown previously, deregulation of the JAK/STAT pathway is central to MPN development and is driven in most cases by activating mutations in
Understanding molecular mechanisms of MPN pathogenesis has stimulated drug development in the field.
Reduction of thrombotic risk is the major goal of therapy in patients with PV and ET, and hydroxyurea (HU) is normally the first-line drug for achieving cytoreduction [98, 99]. In addition, most patients should receive aspirin, if they have no contraindications. In PV, maintaining hematocrit values <45% is an important therapeutic target. Second-line drugs of choice are interferon-α (IFNα) and busulfan [99].
The clinical efficacy of IFNα has been reported since 30 years ago and was improved with the development of pegylated forms [100, 101]. Furthermore, significant reductions of the
RUX showed efficiency in spleen size reduction and symptomatology alleviation, improving quality of life, and overall survival; however, no significant decrease in allele burden was achieved [11, 111, 112]. RUX effects on the malignant clone are modest, side effects (such as anemia and thrombocytopenia) are reported, and drug resistance may appear. Other therapeutic strategies have been developed; they include the discovery of new inhibitors that target specifically mutant JAK2 and the combination of current therapies with other molecules that inhibit components of signaling pathway [105].
Early studies provided some evidence for the increased resistance to apoptosis of PV erythroid progenitor cells: overexpression of BCL-xL in the absence of EPO and a higher sensitivity to the antiapoptotic growth factor IGF-1 [113]. Moreover, Zeuner et al. have shown that erythroid precursors in PV patients with average and high
In susceptible cells, apoptosis is caused by exposure to a JAK inhibitor, which leads to dephosphorylation of BAD, enabling BAD to bind and sequester the antiapoptotic protein BCL-xL. On the other side, in potent cells, RAS effector pathways keep BAD phosphorylation in the presence of JAK inhibitors, maintaining a specific dependence on BCL-xL for survival. So, downstream regulation of BCL-xL, more precisely BCL-xL inhibition, might be the key against resistance to JAK inhibition by either co-inhibition of JAK and RAS effector in AKT and ERK pathways or by direct inhibition of BCL-xL inducing apoptosis [116].
At present, there are over 1500 clinical trials evaluating various drug effects on myeloproliferative neoplasms registered at clinicaltrials.gov. Some of them might be successful due to targeting different apoptotic pathways or by targeting simultaneously different types of PCD.
Plitidepsin is a synthetically produced anticancer agent [117], a cyclodepsipeptide related to didemnins, commercialized as Aplidin® (PharmaMar, S.A., Madrid, Spain). Plitidepsin induces dose-dependent cell-cycle arrest and an acute apoptotic process. These effects rely on the induction of early oxidative stress, the rapid activation of Rac1 GTPase, and the sustained activation of JNK and p38/MAPK, which finally result in caspase-dependent apoptosis [118, 119]. JNK phosphorylation can be seen as early as 5–10 minutes after exposure to the compound. The activation of JNK and p38/MAPK is associated with increase in reactive oxygen species and a decrease in reduced form of glutathione [120].
Recent studies have led researchers to hypothesize that the primary target of plitidepsin could be the eukaryotic elongation factor 1A2 (eEF1A2), which is overexpressed in tumors and supports tumor cell proliferation while inhibiting apoptosis [121]. eEF1A2 seems to be an interesting target for therapy and may also be a biomarker predicting drug sensitivity. Aplidin®/Plitidepsin was investigated for its effect (safety and tolerability) on bone marrow or peripheral blood cells as well as assessed the response rate in patients with PMF, post-PV MF, or post-ET MF, in phase II/open label single agent clinical trial (NCT01149681). Although the drug was well tolerated, the trial was prematurely terminated due to the low response rate [122].
Navitoclax is an orally active, synthetic small molecule and an antagonist of the apoptosis suppressor proteins BCL-2, BCL-xL, and BCL-w, which are frequently overexpressed in a wide variety of cancers, including myeloid ones, and are linked to drug resistance. Inhibition of these apoptosis suppressors prevents their binding to the apoptotic effectors BAX and BAK proteins, thereby triggering apoptotic processes in cells overexpressing BCL-2, BCL-xL, and BCL-w. This eventually reduces tumor cell proliferation. Navitoclax (ABT-263) and RUX are currently evaluated in combination for efficacy, safety, and tolerability on spleen volume as assessed by magnetic resonance imaging (MRI) in participants with MF in a phase II/open label clinical trial (NCT03222609).
Obatoclax (GX15–070) is a BH3-mimetic designed to target and counteract antiapoptotic BCL-2 proteins. Obatoclax is an MCL-1 antagonist [123] and downregulates p53, and it has a dual mechanism of action, being capable to induce apoptosis or autophagy [124]. On the other side, obatoclax accumulates in lysosomes inducing their alkalinization and inhibiting their function [125]. Parikh et al. conducted a multicenter, open-label, noncomparative phase II study (NCT00360035) of obatoclax in patients with MF. Unfortunately, obatoclax exhibited no significant clinical activity at the tested dose and schedule [126].
Other phase I trial (NCT02436135) investigated the combination of RUX with idelalisib, a PI3K delta inhibitor, as therapy for intermediate to high-risk PMF, post-PV MF, or post-ET MF with progressive or relapsed disease [127].
PIM inhibitors have shown preclinical synergy with JAK inhibitors, as well as the ability to overcome JAK inhibitor resistance in MPN cell lines. PIM regulate JAK/STAT signaling and are involved in oncogenesis through phosphorylation of cell cycle regulators, activation of antiapoptotic proteins, and enhancement of MYC expression [97]. A phase 1b study of RUX plus PIM inhibitor PIM447, or RUX plus CDK4/6 inhibitor ribociclib (LEE011), or the combination of all three is underway in several non-U.S. countries (NCT02370706).
As PI3K/AKT/mTOR signaling is markedly activated in MPNs, small molecule inhibitors of the proteins involved in this pathway have been tested in MF with promising results. Thus, mTOR inhibitor everolimus, as single therapeutic agent, was able to induce responses, in terms of reducing constitutional symptoms and the degree of leukocytosis, thrombocytosis, and anemia, in 23% of patients in a phase I/II clinical trial. Due to the preclinically proved synergic effects of PI3K/AKT/mTOR inhibitors and JAK inhibitors, several clinical studies were initiated: PI3K inhibitor TGR-1202 in combination with RUX (NCT02493530), PI3K inhibitor buparlisib with RUX (NCT01730248), PI3K inhibitor INCB050465 and RUX (NCT02718300), and selective PI3Kδ inhibitor TGR-1202 and RUX (NCT02493530). Preliminary results of buparlisib and RUX phase 1b study indicated that this drug association was well tolerated, and ≥ 50% reduction in splenomegaly was observed in 70% of JAK-inhibitor naive patients and 54% of patients who did not previously respond to JAK2 inhibitor monotherapy [97, 127].
RAF/MEK/ERK pathway is another signaling cascade activated in MPNs by the increased JAK/STAT signaling. Therefore, MEK inhibitors were tested in different murine models, either alone or in combination with JAK inhibitors, showing a decrease in bone marrow fibrosis, inhibition of malignant cell growth, and HSC function recovery, associated with a prolonged survival. Moreover, a new trial that combines the MEK inhibitor selumetinib with the DNA hypomethylating agent azacitidine is soon expected [97].
Preclinical studies reveal a central role for tumor necrosis factor alfa (TNF-α) in promoting clonal dominance of
SMAC-mimetics are novel apoptosis-inducing agents that stimulate the ubiquitinylation and proteasomal degradation of cellular inhibitors of apoptosis (IAPs) [102], proteins that play an important role in tumor cell resistance to cytotoxicity mediated by TNF superfamily cytokines. These agents have been shown to sensitize cancer cells to TNF family-induced apoptosis [103]. Results from a phase II trial of the SMAC-mimetic LCL-161 in patients with intermediate or high-risk MF intolerant of, ineligible for, or relapsed/refractory to JAK inhibitors were recently presented. Six of sixteen evaluated patients (38%) had objective responses, obtaining clinical improvement and in one case cytogenetic remission [128].
Resistance of hematologic malignancies to PCD significantly limits the efficacy of chemotherapy. As the majority of chemotherapeutic drugs trigger apoptosis, the observed resistance may indicate that novel therapeutic strategies to reactivate nonapoptotic PCD or at least combined therapeutic strategies able to attack simultaneously different mechanisms might be better approaches to eradicate malignant cells.
Deregulation of pro- and anti-PCD genes involved in cell resistance to cell death and accumulation of myeloid cells in MPNs is continuously clarified by intense exploration of the modifications affecting different types of PCD pathways involved in myeloid proliferation. At the same time, comprehension of the network of signaling pathways involved in etiology and drug resistance of these disorders facilitate a more efficient exploitation of the knowledge, using combined and synergic, targeted therapeutic strategies.
We gratefully acknowledge the funding from the project Competitiveness Operational Programme (COP) A1.1.4. ID: P_37_798 MyeloAL-EDiaProT, Contract 149/26.10.2016, (SMIS: 106774), MyeloAL Project.
All the authors contributed equally to this manuscript.
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