1. Introduction
In 1927, the Swiss pediatrician Guido Fanconi first reported a family with aplastic anemia and physical anomalies known as FA now, as reviewed by Lobitz et al (Lobitz and Velleuer 2006). FA is a chromosomal fragility disorder characterized by cytopenia, progressive bone marrow failure (BMF) under production, variable developmental anomalies and a strong propensity for cancer. The prevalence of FA is 1 to 5 per million, and heterozygous carrier frequency is about 1 in 300. Clinically, FA patients develop heterogeneous manifestations. 80% of FA patients develop progressive BMF with a mean age of death occurring at 19 years (D'Andrea, Dahl et al. 2002; Bagby and Alter 2006;Giri, Batista et al. 2007). The other 20% of patients usually die of malignancies resulting from the acquisition of myeloid cell leukemia particularly acute myelogenous leukemia and myelodysplastic syndrome. In addition, FA Patients are susceptible to solid tumors, including gynecologic squamous cell carcinoma, head and neck squamous cell carcinoma, esophageal carcinoma, liver tumors, brain tumors, skin tumors, and renal tumors(Kutler, Singh et al. 2003).
To date, at least 15 distinct
FA pathway is inactive in normal cells but turned on during the S phase of cell cycle or in the presence of DNA damage proteins, and it also plays a pivotal role in DNA repair pathway in cellular defense against DNA interstrandcrosslinkers(Moldovan and D'Andrea 2009; Kee and D'Andrea 2010). Following the activation, eight of 15
2. FANC genes regulate HSC/HPC functions
Because of the earlier bone marrow failure and the predisposition to malignancy, especially the high risk of developing acute myeloid leukemia(AML), FA has been clinically categorized as a hematopoietic disease due to hematopoietic dysfunction. The defective hematopoietic functions are known related to an excess of genetic instability. FA bone marrow cells have clonal evolution, which predispose patients to the development of malignancies. Vinciguerra et al reported an increased number of ultrafine DNA bridges and binucleated cells in both bone marrow stromal cells from FA patients and in primary murine FA pathway-deficient hematopoietic stem/progenitor cells (HSCs/HPCs)(Vinciguerra, Godinho et al. 2010). Using primary and immortalized cell cultures as well as
3. Murine models of FA
To our best knowledge, 9 of 15
Cheng et al first created
Two different
Fancd2 undergoes monoubiquitylation by the complex and is targeted into nuclear foci and co-localizes with Brca1.
Although
As described above, differing from FA patients who often spontaneously develop bone marrow failure in their lives, most of the models have relatively normal hematological function. It is possible that FA proteins have divergent functions which are independent of FANCD2/FANCI monoubiquitination in hematopoietic cells. To test if deletion of multiple
4. Bone marrow microenvironmental abnormalities in hematopoietic diseases
Hematopoiesis is a dynamic and highly regulated process,which relies on the ordered self-renewal and differentiation of HSCs/HPCs within the bone marrow (BM) (Kotton, Ma et al. 2001; Krause 2002; Zhang, Niu et al. 2003; Li and Li 2006; Yin and Li 2006). This process involves intrinsic and extrinsic cues including both cellular and humoral regulatory signals generated by the HSC microenvironment, also known as “niche”. The concept of hematopoietic niche has been proposed in the 1970s (Schofield 1978). Studies have shown that the cellular composition of this “niche” contains heterogeneous populations, including endothelial cells, osteoblasts, adipocytes (Calvi, Adams et al. 2003; Zhang, Niu et al. 2003; Arai, Hirao et al. 2005; Sacchetti, Funari et al. 2007), and mesenchymal stem/progenitor cells (MSPCs) (Badillo and Flake 2006),a common progenitor for many of these cells composing the HSC niche. The regulatory signals of the BM microenvironment represent a demarcated anatomical compartment that provides stimulatory signals to HSCs via the following mechanisms: (1) cell/cell direct interactions, (2) secreting soluble factors, and (3) extracellular matrix. These cellular and humoral regulatory signals dictate HSC cell fate, such as self-renewal, proliferation, differentiation, and apoptosis.
The osteoblastic niche and the vacular niche are well described by independent groups (Heissig, Hattori et al. 2002; Calvi, Adams et al. 2003; Zhang, Niu et al. 2003;Avecilla, Hattori et al. 2004).Studies have shown that BM microenvironment is critical for the physiologic as well as pathologic development of hematopoiesis through the following mechanisms: cell/cell interactions, soluble factors and extracellular matrix(Koh, Choi et al. 2005; Williams and Cancelas 2006). There is increasing evidence suggesting a role of the hematopoietic microenvironment in initiating hematopoietic disorders, such as myeloproliferative disorders (MPD).
Recently, using a murine model in which Dicer1 was specifically deleted in osteoprogenitors, Raaijmakers et al demonstrated that bone marrow microenvironment plays a causative role in the development of myelodysplasia and secondary leukaemia(Raaijmakers, Mukherjee et al. 2010). The vascular microvessel density is increased in the bone marrow of many hematopoietic disorders including AML, acute lymphoblastic leukemia (ALL), myelosyndromes (MDS) and myeloproliferative neoplasms (MPN). The adipocytes are also found to be accumulated in BMF (Li, Chen et al. 2009). Although the mechanism for the accumulation of adipocytes in bone marrow is still largely unknown, the accumulated adipocytes may act as negative regulators in the hematopoietic microenvironment (Naveiras, Nardi et al. 2009).
5. Dysregulated bone marrow microenvironment in FA patients and FA murine models
Besides the hematopoietic defects, mesenchymal tissue-derived congenital malformations are also prevalent in FA patients, such as the renal/limb abnormalities and short stature. Despite these clinical observations suggesting multiple mesenchymal defects, little attention has been directed to the association between the pathological HSC functions and the microenvironment in FA.
Using a murine model with targeted disruption of the
Consistently, study by Zhang et al showed that MSPCs derived from the bone marrow of
Using the MSPCs derived from patients with
6. Current treatments for FA
The long-term curative therapy for the BMF of FA patients is HSC transplantation, ideally from an HLA-matched sibling(Gluckman, Broxmeyer et al. 1989; Davies, Khan et al. 1996; Guardiola, Pasquini et al. 2000; Kutler, Singh et al. 2003; Mathew 2006) Allogeneic BM transplantation (BMT) or cord blood (CB) transplantation is available to up-to 30% of FA patients. However, allogeneic BMT or CB transplantation is frequently associated with an increased risk of secondary cancers, particularly squamous cell carcinoma of the head and neck(Kutler, Auerbach et al. 2003; Rosenberg, Socie et al. 2005). Since the conditioning regimens such as irradiation clearly heightens the risk of transformation of the ongoing genetic susceptibility of non-hematopoietic tissue. This complication is even more severe in high-risk FA patients, transplanted with non-matched donors and those develop chronic graft-versus-host disease. Therefore, even with successful allogeneic transplantation for BMF, the risk of secondary malignancies results in a high mortality over 10-15 years. Gene therapy using autologous HSCs is a second theoretical modality to correct defects in the HSC compartment. Transplantation of genetically corrected autologous HSCs without genotoxic conditioning regiments could provide a therapeutic strategy that avoids the increased risks of secondary cancer(Si, Ciccone et al. 2006). However, a significant obstacle for this therapy is the limited number of HSCs that can be harvested from mobilized blood or BM. In addition, in preliminary phase 1 clinical trials in FANCC and FANCA patients using retroviral mediated gene transfer, despite an efficient gene transfer of the mobilized progenitors (40-80%), and no long-term engraftment of retroviral marked stem cells was achieved(Liu, Kim et al. 1999; Williams, Croop et al. 2005; Kelly, Radtke et al. 2007). Although inefficient gene transfer of repopulating HSCs can not be excluded, inefficient engraftment and homing of exogenous genetically modified cells could also be contributory, particularly given the low numbers of HSC targets that are available for gene transfer/transplantation(Gothot, Pyatt et al. 1998; Glimm, Oh et al. 2000; Orschell-Traycoff, Hiatt et al. 2000). Since mesenchymalstem/progenitor cells were excluded in these studies, it is possible that the lack of an appropriate microenvironment could have impaired the ability of transduced cells to home and proliferate
7. Biology of MSPCs and their potential clinical application in transplantation therapy for FA patients
Friedenstein and colleagues first reported a rare, plastic-adherent and fibroblast-like subpopulation expanded from the culture of bone marrow in 1970s (Friedenstein, Chailakhjan et al. 1970), this type of stromal cells, now commonly known as MSCs/MSPCs, has captivated more and more investigators, especially in the past two decades. As a group cells with heterogeneity, three criteria have been proposed to define human MSPCs, including plastic-adherence, surface expression of CD105, CD73 and CD90, and the absence of CD45, CD34, CD14 or CD11b, CD79a, CD19, CD14 or CD11b and HLA-DR, and trilineage differentiation to osteoblasts, adipocytes and chondrocytes
It is well known that MSPCs lack expression of MHC class II and most of the classical co-stimulatory molecules such as CD80, CD86, or CD40 (Pittenger, Mackay et al. 1999; Tse, Pendleton et al. 2003). This phenotypic characteristic endows MSPCs with nonimmunogenicity, and therefore transplantation of MSPCs into allogeneic host could be implemented without using immunosuppressive agents. MSPCs are known promote the reconstitution of hematopoiesis. We have recently provided evidence for the first time that
8. Future directions
FA is an inherited disease caused by germ-line mutations in
References
- 1.
Agoulnik A. I. Lu B. et al. 2002 A novel gene, Pog, is necessary for primordial germ cell proliferation in the mouse and underlies the germ cell deficient mutation, gcd." 11 24 3047 3053 - 2.
Arai F. Hirao A. et al. 2005 Regulation of hematopoiesis and its interaction with stem cell niches." 82 5 371 376 - 3.
Auerbach A. D. Buchwald M. et al. 2002 Fanconianemia. In: Vogelstein B, Kinzler KW, eds." (New YorK: McGraw-Hill, Inc.): 289 306 - 4.
Avecilla S. T. Hattori K. et al. 2004 Chemokine-mediated interaction of hematopoietic progenitors with the bone marrow vascular niche is required for thrombopoiesis." 10 1 64 71 - 5.
Badillo A. T. Flake A. W. 2006 The regulatory role of stromal microenvironments in fetal hematopoietic ontogeny." 2 3 241 246 - 6.
Bagby G. C. Alter B. P. 2006 Fanconianemia." 43 147 156 - 7.
Agoulnik A. I. Lu B. et al. 2002 A novel gene, Pog, is necessary for primordial germ cell proliferation in the mouse and underlies the germ cell deficient mutation, gcd." 11 24 3047 3053 - 8.
Arai F. Hirao A. et al. 2005 Regulation of hematopoiesis and its interaction with stem cell niches." 82 5 371 376 - 9.
Auerbach A. D. Buchwald M. et al. 2002 Fanconianemia. In: Vogelstein B, Kinzler KW, eds." (New YorK: McGraw-Hill, Inc.): 289 306 - 10.
Avecilla S. T. Hattori K. et al. 2004 Chemokine-mediated interaction of hematopoietic progenitors with the bone marrow vascular niche is required for thrombopoiesis." 10 1 64 71 - 11.
Badillo A. T. Flake A. W. 2006 The regulatory role of stromal microenvironments in fetal hematopoietic ontogeny." 2 3 241 246 - 12.
Bagby G. C. Alter B. P. 2006 Fanconianemia." 43 147 156 - 13.
Bagby G. C. Jr Segal G. M. et al. 1993 Constitutive and induced expression of hematopoietic growth factor genes by fibroblasts from children with Fanconianemia." 21 11 1419 1426 - 14.
Bakker S. T. van de Vrugt H. J. et al. 2009 Fancm-deficient mice reveal unique features of Fanconianemia complementation group M." 18 18 3484 3495 - 15.
Barroca V. Mouthon M. A. et al. 2012 Impaired functionality and homing of Fancg-deficient hematopoietic stem cells." 21 1 121 135 - 16.
Bouwman P. Drost R. et al. 2011 Loss of 53 partially rescues embryonic development of Palb2 knockout mice but does not foster haploinsufficiency of Palb2 in tumour suppression." 224 1 10 21 - 17.
Calvi L. M. Adams G. B. et al. 2003 Osteoblastic cells regulate the haematopoietic stem cell niche." 425 6960 841 846 - 18.
Chen M. Tomkins D. J. et al. 1996 Inactivation of Fac in mice produces inducible chromosomal instability and reduced fertility reminiscent of Fanconi anaemia." 12 4 448 451 - 19.
Cheng N. C. van de Vrugt H. J. et al. 2000 Mice with a targeted disruption of the Fanconianemia homolog Fanca." 9 12 1805 1811 - 20.
D’Andrea A. D. 2010 Susceptibility pathways in Fanconi’sanemia and breast cancer." 362 20 1909 1919 - 21.
D’Andrea A. D. Dahl N. et al. 2002 Marrow failure." 58 72 - 22.
Davies S. M. Khan S. et al. 1996 Unrelated donor bone marrow transplantation for Fanconianemia." 17 1 43 47 - 23.
Dominici M. Le Blanc K. et al. 2006 Minimal criteria for defining multipotentmesenchymal stromal cells. The International Society for Cellular Therapy position statement." 8 4 315 317 - 24.
Du W. Adam Z. et al. 2008 Oxidative stress in Fanconianemiahematopoiesis and disease progression." 10 11 1909 1921 - 25.
Friedenstein A. J. Chailakhjan R. K. et al. 1970 The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells." 3 4 393 403 - 26.
Giri N. Batista D. L. et al. 2007 Endocrine Abnormalities in Patients with FanconiAnemia." 92 7 2624 2631 - 27.
Glimm H. Oh I. H. et al. 2000 Human hematopoietic stem cells stimulated to proliferate in vitro lose engraftment potential during their S/G(2)/M transit and do not reenter G(0)." 96 13 4185 4193 - 28.
Gluckman E. Broxmeyer H. A. et al. 1989 Hematopoietic reconstitution in a patient with Fanconi’sanemia by means of umbilical-cord blood from an HLA-identical sibling." 321 17 1174 1178 - 29.
Gothot A. Pyatt R. et al. 1998 Assessment of proliferative and colony-forming capacity after successive in vitro divisions of single human CD34+ cells initially isolated in G0." 26 7 562 570 - 30.
Guardiola P. Pasquini R. et al. 2000 Outcome of 69 allogeneic stem cell transplantations for Fanconianemia using HLA-matched unrelated donors: a study on behalf of the European Group for Blood and Marrow Transplantation." 95 2 422 429 - 31.
Haneline L. S. Gobbett T. A. et al. 1999 Loss of FancC function results in decreased hematopoietic stem cell repopulating ability." 94 1 1 8 - 32.
Heissig B. Hattori K. et al. 2002 Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand." 109 5 625 637 - 33.
Houghtaling S. Timmers C. et al. 2003 Epithelial cancer in Fanconianemia complementation group D2 (Fancd2) knockout mice." 17 16 2021 2035 - 34.
Kee Y. D’Andrea A. D. 2010 Expanded roles of the Fanconianemia pathway in preserving genomic stability." 24 16 1680 1694 - 35.
Kelly P. F. Radtke S. et al. 2007 Stem cell collection and gene transfer in Fanconianemia." 15 1 211 219 - 36.
Kim Y. Lach F. P. et al. 2011 Mutations of the SLX4 gene in Fanconianemia." 43 2 142 146 - 37.
Koh S. H. Choi H. S. et al. 2005 Co-culture of human CD34+ cells with mesenchymal stem cells increases the survival of CD34+ cells against the 5-aza-deoxycytidine- or trichostatin A-induced cell death." 329 3 1039 1045 - 38.
Kook H. 2005 Fanconianemia: current management." 1 108 110 - 39.
Koomen M. Cheng N. C. et al. 2002 Reduced fertility and hypersensitivity to mitomycin C characterize Fancg/Xrcc9 null mice." 11 3 273 281 - 40.
Kopen G. C. Prockop D. J. et al. 1999 Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate into astrocytes after injection into neonatal mouse brains." 96 19 10711 10716 - 41.
Kotton D. N. Ma et B. Y. al 2001 Bone marrow-derived cells as progenitors of lung alveolar epithelium." 128 24 5181 5188 - 42.
Krause D. S. 2002 Plasticity of marrow-derived stem cells." 9 11 754 758 - 43.
Kutler D. I. Auerbach A. D. et al. 2003 High incidence of head and neck squamous cell carcinoma in patients with Fanconianemia." 129 1 106 112 - 44.
Kutler D. I. Singh B. et al. 2003 A 20-year perspective on the International FanconiAnemia Registry (IFAR)." 101 4 1249 1256 - 45.
Lecourt S. Vanneaux V. et al. 2010 Bone marrow microenvironment in fanconianemia: a prospective functional study in a cohort of fanconianemia patients." 19 2 203 208 - 46.
Li Y. Chen S. et al. 2009 Mesenchymal stem/progenitor cells promote the reconstitution of exogenous hematopoietic stem cells in Fancg-/- mice in vivo." 113 10 2342 2351 - 47.
Li Z. Li L. 2006 Understanding hematopoietic stem-cell microenvironments." 31 10 589 595 - 48.
Liu J. M. Kim S. et al. 1999 Engraftment of hematopoietic progenitor cells transduced with the Fanconianemia group C gene (FANCC)." 10 14 2337 2346 - 49.
Lobitz S. Velleuer E. 2006 Guido Fanconi (1892-1979): a jack of all trades." 6 11 893 898 - 50.
Mathew C. G. 2006 Fanconi anaemia genes and susceptibility to cancer." 25 43 5875 5884 - 51.
Meetei A. R. Levitus M. et al. 2004 X-linked inheritance of Fanconianemia complementation group B." 36 11 1219 1224 - 52.
Milsom M. D. Lee A. W. et al. 2009 Fanca-/- hematopoietic stem cells demonstrate a mobilization defect which can be overcome by administration of the Rac inhibitor NSC23766." 94 7 1011 1015 - 53.
Moldovan G. L. D’Andrea A. D. 2009 How the fanconianemia pathway guards the genome." 43 223 249 - 54.
Munoz-Elias G. Marcus A. J. et al. 2004 Adult bone marrow stromal cells in the embryonic brain: engraftment, migration, differentiation, and long-term survival." 24 19 4585 4595 - 55.
Navarro S. Meza N. W. et al. 2006 Hematopoietic dysfunction in a mouse model for Fanconianemia group D1." 14 4 525 535 - 56.
Naveiras O. Nardi V. et al. 2009 Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment." 460 7252 259 263 - 57.
Orschell-Traycoff C. M. Hiatt K. et al. 2000 Homing and engraftment potential of Sca-1(+)lin(-) cells fractionated on the basis of adhesion molecule expression and position in cell cycle." 96 4 1380 1387 - 58.
Parmar K. Kim J. et al. 2010 Hematopoietic stem cell defects in mice with deficiency of Fancd2 or Usp1." 28 7 1186 1195 - 59.
Pittenger M. F. Mackay A. M. et al. 1999 Multilineage potential of adult human mesenchymal stem cells." 284 5411 143 147 - 60.
Pulliam-Leath A. C. Ciccone S. L. et al. 2010 Genetic disruption of both Fancc and Fancg in mice recapitulates the hematopoietic manifestations of Fanconianemia." 116 16 2915 2920 - 61.
Raaijmakers M. H. Mukherjee S. et al. 2010 Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia." 464 7290 852 857 - 62.
Rantakari P. Nikkila J. et al. 2010 Inactivation of Palb2 gene leads to mesoderm differentiation defect and early embryonic lethality in mice." 19 15 3021 3029 - 63.
Rio P. Segovia J. C. et al. 2002 In vitro phenotypic correction of hematopoietic progenitors from Fanconianemia group A knockout mice." 100 6 2032 2039 - 64.
Rosenberg P. S. Socie G. et al. 2005 Risk of head and neck squamous cell cancer and death in patients with Fanconianemia who did and did not receive transplants." 105 1 67 73 - 65.
Sacchetti B. Funari A. et al. 2007 Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment." 131 2 324 336 - 66.
Sasaki M. S. 1975 Is Fanconi’s anaemia defective in a process essential to the repair of DNA cross links?" 257 5526 501 503 - 67.
Schofield R. 1978 The relationship between the spleen colony-forming cell and the haemopoietic stem cell." 4 1-2 7 25 - 68.
Schroeder T. M. Anschutz F. et al. 1964 Spontaneous chromosome aberrations in familial panmyelopathy." 1 2 194 196 - 69.
Sharan S. K. Morimatsu M. et al. 1997 Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2." 386 6627 804 810 - 70.
Si Y. Ciccone S. et al. 2006 Continuous in vivo infusion of interferon-gamma (IFN-gamma) enhances engraftment of syngeneic wild-type cells in Fanca-/- and Fancg-/- mice." 108 13 4283 4287 - 71.
Stoepker C. Hain K. et al. 2011 SLX4, a coordinator of structure-specific endonucleases, is mutated in a new Fanconianemia subtype." 43 2 138 141 - 72.
Tse W. T. Pendleton J. D. et al. 2003 Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation." 75 3 389 397 - 73.
Vaz F. Hanenberg H. et al. 2010 Mutation of the RAD51C gene in a Fanconianemia-like disorder." 42 5 406 409 - 74.
Vinciguerra P. Godinho S. A. et al. 2010 Cytokinesis failure occurs in Fanconianemia pathway-deficient murine and human bone marrow hematopoietic cells." 120 11 3834 3842 - 75.
Whitney M. A. Royle G. et al. 1996 Germ cell defects and hematopoietic hypersensitivity to gamma-interferon in mice with a targeted disruption of the Fanconianemia C gene." 88 1 49 58 - 76.
Williams D. A. Cancelas J. A. 2006 Leukaemia: niche retreats for stem cells." 444 7121 827 828 - 77.
Williams D. A. Croop J. et al. 2005 Gene therapy in the treatment of Fanconianemia, a progressive bone marrow failure syndrome." 7 5 461 466 - 78.
Wong J. C. Alon N. et al. 2003 Targeted disruption of exons 1 to 6 of the FanconiAnemia group A gene leads to growth retardation, strain-specific microphthalmia, meiotic defects and primordial germ cell hypoplasia." 12 16 2063 2076 - 79.
Yang Y. Kuang Y. et al. 2001 Targeted disruption of the murine Fanconianemia gene, Fancg/Xrcc9." 98 12 3435 3440 - 80.
Yin T. Li L. 2006 The stem cell niches in bone." 116 5 1195 1201 - 81.
Zhang J. Niu C. et al. 2003 Identification of the haematopoietic stem cell niche and control of the niche size." 425 6960 836 841 - 82.
Zhang Q. S. Marquez-Loza L. et al. 2010 Fancd2-/- mice have hematopoietic defects that can be partially corrected by resveratrol." 116 24 5140 5148 - 83.
Zhang X. Shang X. et al. 2008 Defective homing is associated with altered Cdc42 activity in cells from patients with Fanconianemia group A." 112 5 1683 1686