Open access peer-reviewed chapter

Function of the Stem Cell Transcription Factor SALL4 in Hematopoiesis

Written By

Jianchang Yang

Submitted: November 13th, 2017 Reviewed: March 13th, 2018 Published: November 5th, 2018

DOI: 10.5772/intechopen.76454

Chapter metrics overview

1,010 Chapter Downloads

View Full Metrics

Abstract

SALL4 is a zinc finger DNA-binding protein that has been well characterized in development and in embryonic stem cell (ESC) maintenance. Notably, SALL4 may be one of the few genes that are also involved in tissue stem cells in adults, and SALL4 protein expression has been correlated with the presence of stem and progenitor cell populations in various organ systems and also in human cancers. In normal hematopoiesis, SALL4 expression is restricted to the rare hematopoietic stem/progenitor cell (HSC/HPC) fractions but is rapidly silenced following lineage differentiation. In hematopoietic malignancies, however, SALL4 is persistently expressed and its expression levels are linked with deteriorated disease status. Furthermore, SALL4 activation participates in the pathogenesis of tumor initiation and disease progression. This chapter summarizes recent advances in our knowledge of SALL4 biology with a focus on its regulatory functions in normal and leukemic hematopoiesis. A better understanding of SALL4’s biologic functions and mechanisms is needed to facilitate the development of advanced therapies in future.

Keywords

  • pluripotency
  • leukemogenesis
  • hematopoietic stem/progenitor cell
  • MLL-rearrangement
  • epigenetic
  • histone methylation
  • DNA methylation
  • differentiation
  • zinc finger domain

1. Introduction

SALL4 is one of four human homologs (SALL-1, -2, -3, -4) of the Drosophila region-specific gene Spalt(sal). In Drosophila, salis a homeotic gene essential for development of posterior head and anterior tail segments. As a DNA-binding transcription factor, the SALL4 protein is characterized by multiple Cys2His2 zinc finger (C2H2-ZF) domain distributed over the entire protein [1, 2, 3]. In mammals, the expression of SALL4 has been primarily detected in ESCs and in adult tissue “stem-like” cells, where it mainly activates pluripotency and/or multipotency genes and suppresses differentiation-related genes, thereby modulating the cell “stemness” in development and in tissue generation [4, 5, 6, 7, 8]. In humans, heterozygous SALL4 mutation has been linked to Okihiro syndrome, Holt-Oram syndrome, acro-renal-ocular syndrome, and IVIC syndrome, all characterized by multiple organ malformations [9, 10, 11]. While normally downregulated or no longer expressed in fully differentiated somatic cells, abnormal reactivation of SALL4 in adult cells may lead to malignancy. To date, aberrant SALL4 expression has been detected in over 10 types of human solid tumors and in several common types of leukemias, and SALL4 has been considered a useful biomarker for these diseases [7, 8, 12, 13]. In addition, studies suggest that SALL4 may be a therapeutic target in treating human leukemias [12, 13]. For these reasons, it will be important to understand how SALL4, a critical pluripotency factor, exerts its effects in different cell contexts, and how we can effectively translate our knowledge gains into treatment breakthroughs in future.

Advertisement

2. SALL4 roles in stem cells and development

2.1. The roles of SALL4 in ESC property maintenance and embryonic development

SALL4 has been one of the most studied transcriptional regulators in ESC self-renewal and pluripotency maintenance. It has been reported that in human ESCs, a well-controlled SALL4/OCT4 transcription regulatory loop balances proper expression dosage of SALL4 and OCT4; and reduction of SALL4, like OCT4, results in re-specification of ESCs to the trophoblast lineage [14, 15, 16, 17]. In mouse ESC studies, chromatin immunoprecipitation coupled to microarray hybridization (ChIP-on-chip) revealed that SALL4 binds to about twice as many gene promoters as NANOG and binds about four times more genes than OCT4; and the three factors were found to form heteromeric protein complex in regulating stem cell pluripotency. Further, SALL4 binds many genes that are regulated by chromatin-based epigenetic events mediated by cohesin complex, polycomb-repressive complexes 1 and 2 (PRC1 and PRC2), and bivalent domains [18, 19]. Thus, SALL4 plays a diverse role in regulating stem cell pluripotency (see Figure 1).

Figure 1.

SALL4 plays a variety of regulatory functions in maintaining and/or reprogramming cells to pluripotency. PRC: polycomb-repressive complexes.

In early embryonic development, SALL4 expression in mouse is detected at as early as the two cell stage. At the blastocyst stage, SALL4 expression becomes enriched in the inner cell mass (ICM) and the trophectoderm [17, 20, 21, 22]. Reduction of SALL4 in oocytes and ESCs results in early embryo defects, and disruption of both Sall4alleles causes embryonic lethality during peri-implantation [23, 24, 25]. SALL4 is also expressed in extraembryonic endoderm (XEN) cells, where it participates in cell fate decision by simultaneously activating pluripotency-maintaining factors and silencing endoderm lineage-associated factors such as GATA6, GATA4, and SOX17 [26, 27]. During subsequent stages, heterozygous disruption of Sall4allele leads to multi-organ malformations including limb and heart defects, which model human disease [25]. It has been reported that TBX5, a gene encoding a T-box transcription factor, regulates SALL4 expression in the developing forelimb and heart, and interacts with SALL4 to synergistically regulate downstream gene expression [24, 25, 28].

2.2. SALL4 is a potent regulator in reprogramming somatic cells to pluripotency

Decreased SALL4 expression in ESCs has been shown to downregulate the expression levels of Oct4, Sox2, Klf4, and c-Myc (OSKM), the four proteins capable of reprogramming murine somatic cells to an induced pluripotent state [18, 29]. Consistently, knockdown of SALL4 in fibroblasts decreased the efficiency of induced pluripotent stem cell (iPSC) generation, while overexpression of SALL4 significantly increased iPSC generation [30, 31]. In a recent study by Shu et al., the GATA family members GATA4 and GATA6 have been found to substitute for OCT4 in mouse somatic reprogramming, and SALL4 is identified as a major target gene of the GATA members [32]. In another study by Buganim et al., ectopic expression of SALL4, NANOG, ESRRB, and LIN28 in mouse fibroblasts generated high-quality iPSCs more efficiently than the combination of OSKM [33]. Similarly, Mansour et al., showed that the combined overexpression of SALL4 with stem cell factors SALL1, UTF1, NANOG and MYC also replaced exogenous OSK expression and generated chimaera formation- competent iPSC clones [34]. Together, these studies suggest that SALL4 not only plays a role in ESC property maintenance, but its overexpression also drives reprogramming of somatic cells toward a stem cell-like fate (see Figure 1).

2.3. SALL4 regulates distinct transcriptional networks in ESCs and XEN cells

SALL4 appears to be unique among the core ESC pluripotency regulators because it is also expressed in non-ESC stem cell fractions where Oct4 and/or Nanog are silenced. These include XEN cells, mesodermal progenitor cells [35], embryonic cardiac progenitor cells [36], fetal liver stem/progenitor cells [27], and adult stem cells such as bone marrow HSCs/HPCs [37]. In these cells, SALL4 regulates downstream networks in a cell type-specific manner. Genome-wide promoter binding assays in murine ESCs and XEN cells revealed that SALL4 regulates disparate gene sets in these cells, and down-regulation of SALL4 targets in the respective cell types induced differentiation [26]. Also consistent with the previous report [18], Sall4, Oct4, Sox2, and Nanog in murine ESCs formed a crucial interconnected autoregulatory network. In XEN cells however, SALL4 regulates the key XEN lineage-associated genes Gata4, Gata6, Sox7, and Sox17 (see Figure 2). Moreover, transcription assays revealed that SALL4 regulates the expression of more than half of its binding genes in ESCs, but downregulation of SALL4 did not result in similar expression changes in the majority of these genes in XEN cells [26].

Figure 2.

SALL4 binds and regulates distinct target genes in ESCs and XEN cells. Shown are examples of such genes in each cell types. Figure modified from Ref. [26].

Advertisement

3. Functions of SALL4 and its regulated networks in normal hematopoiesis

3.1. The SALL4 isoforms are robust simulators for HSC/HPC ex vivoexpansion

In humans and mice, the SALL4 proteins exist in at least three isoforms termed A, B and C, with SALL4A (full length) and SALL4B (lacks a portion of exon2 sequence) being the most studied [38, 39, 40]. To date, the function of SALL4C isoform (exon2 sequence spliced out) has not been well characterized. In the human blood system, the cellular expressions of SALL4 isoforms have been originally investigated by immunofluorescence staining and qRT-PCR assays, which revealed that both A and B isoforms are highly expressed in bone marrow CD34+CD38− HSCs, downregulated in CD34+CD38+ HPCs, and absent in CD34− differentiated lineage cells. Similarly, the SALL4 -A and -B isoforms in mouse bone marrows were found selectively expressed in the nuclei of Lin-Sca1+cKit+ (LSK) HSCs. The functions of SALL4 in the self-renewal of HSCs/HPCs have been explored. We and others reported that the SALL4 isoforms are robust stimulators for CD34+ (or CD133+) HSCs/HPCs ex vivoexpansion, and the SALL4-mediated cell expansion was associated with enhanced cell engraftment and long-term repopulation capacity in transplanted mice [40, 41, 42, 43, 44]. In mouse model studies, forced overexpression of the SALL4 isoforms in bone marrow LSK cells likewise leads to sustained cell proliferation, as well as enhanced marrow-repopulating potential in vivo[39]. By transcripts assays, the increased HSC/HPC growth was found associated with upregulation of important HSC regulatory genes including HOXB4, NOTCH1, BMI1, RUNX1, CMYC, MEIS1 and NF-YA [39]. Further, in a myeloid progenitor cell line (32D cell) study, overexpression of the SALL4 isoforms blocked granulocyte-colony stimulating factor (G-CSF)-induced granulocytic differentiation, and permitted expansion of undifferentiated cells in the presence of defined cytokines [39, 40]. Thus, the SALL4 isoforms stimulate HSC/HPC proliferation by activating important self-renewal regulators and simultaneously inhibiting cellular differentiation. These studies provide a new avenue for investigating mechanisms of SALL4-regulated HSC/HPC self-renewal and potentially achieving clinically significant expansion of transplantable human HSCs.

3.2. ChIP-on-chip and gene expression assays identified important target genes that are regulated by SALL4

In their study of SALL4 regulated networks in normal hematopoiesis, Gao et al. have sorted human bone marrow and cord blood CD34+ cells, and performed ChIP-on-chip together with gene expression assays . This investigation identified that CD34, RUNX1, HOXA9, and PTEN are SALL4-directed target genes in these cells. In particular, HOXA9 was characterized as a major SALL4 target in normal hematopoiesis . In another study, the polycomb complex protein BMI-1 as a critical SALL4 downstream target has been documented [45]. Chromatin immunoprecipitation coupled with quantitative PCR (ChIP-qPCR) in the 32D myeloid progenitor cells reveals that SALL4 binds to a specific region of Bmi-1gene promoter, and heterozygous disruption of Sall4allele significantly reduced BMI-1 expression in bone marrow cells. Further, in transgenic mice that constitutively overexpress human SALL4B, there is upregulated expression of BMI-1, whose levels increase in the progression from normal to preleukemic (myelodysplastic syndrome [MDS]) and leukemic (acute myeloid leukemia [AML]) stages [45].

3.3. SALL4 roles in normal HSC/HPC capacity maintenance

In human CD34+ cell studies, a shRNA-mediated SALL4 knockdown resulted in decreased in vitromyeloid-colony-forming ability and impaired in vivoengraftment. Further, loss of either SALL4 or its downstream target HOXA9 expression in CD34+ cells shared a similar phenotype. These findings indicate that the role of SALL4 and HOXA9 in normal hematopoiesis is to maintain the HSPCs in an undifferentiated stage with self-renewal capacity [37]. Very recently, the roles of SALL4 in normal hematopoiesis have been further explored using conditional gene targeting approaches in mice [46]. Unexpectedly, wild type Sall4f/f/CreERT2 mice treated with tamoxifen or vav-Cre-mediated (hematopoietic-specific) Sall4−/− mice were all healthy and displayed no significant hematopoietic defects, which contrasts to previous findings from human CD34+ cell studies. Reasons for this discrepancy have not been fully addressed. However, it has been speculated that SALL4 may have a redundant role during homeostasis, which can be compensated by other Sallgene family members, or pretreatmentof gene knockdown may not truly reflect the actual performance of gene functions in vitroor in vivo. On the other hand, some genes may exert aberrant functions only when cells encounter transplantation or replicative stress (see review [47]), and some vav/Cre knockout models may demonstrate hematopoietic defects at late stages [48]. Therefore, it might be necessary to perform serial transplantation and/or stress induction (such as 5-fluorouracil injury) assays with SALL4-deficient cells to fully clarify SALL4 effect and mechanisms in normal HSC capacity maintenance.

Advertisement

4. Functions of SALL4 and its regulated networks in leukemia

4.1. SALL4 is aberrantly expressed in human leukemias

SALL4 is absent in most adult tissues and SALL4 expression in bone marrow is restricted to the rare CD34+ HSCs/HPCs. However, aberrant expression of SALL4 has been detected in various human solid tumors as well as different types of leukemias [49, 50, 51, 52, 53, 54, 55, 56, 57]. In patients with MDS, a group of preleukemic hematologic disorders, a high level of SALL4 expression is detected and correlated with high-risk patients with poor survival [58, 59]. In AML cases, our group and others have reported that SALL4 mRNA or proteins are aberrantly expressed in various AML subtypes (ranging from M1 to M5, the French-American-British [FAB] classification), and SALL4 expression is involved in chromosomal instability and associated with disease status and drug treatments [59, 60, 61, 62, 63, 64, 65]. SALL4 expression is found significantly higher in AML patients with complex karyotype (equal to or more than three aberrant karyotypes) than that in MDS patients with normal karyotype [63]. In chemotherapy cases, it has been reported that SALL4 has the highest expression level in de novo AML patients which then decreases in partial remission (PR), and then even lower in complete remission (CR) [61, 62]. Further, SALL4 was found to decrease throughout the treatment process in the drug responsive group but increase in drug resistant group [62]. In other leukemia cases, aberrant SALL4 expression has been reported in ALK positive anaplastic large cell lymphoma (ALK+ ALCL) [66], B cell acute lymphocytic leukemia (B-ALL), most prominently in B-ALL patients with TEL-AML1 translocation, which is the most common genetic abnormality in pediatric B-ALL [67, 68]. SALL4 expression is also detected in precursor B-cell (but not T-cell) lymphoblastic leukemia/lymphomas [61]. In addition, SALL4 expression has been detected in patient samples from blastic stage of chronic myeloid leukemia (CML), as opposed to the chronic phase, and in samples from CML patients who have achieved complete remission or those who have tyrosine kinase inhibitor resistance [61, 69, 70].

4.2. Role of SALL4 in transgenic model and in MLL-rearranged leukemia

Given the detection of aberrant SALL4 expression in leukemia patients, our research group has previously investigated transgenic mice that overexpress either human SALL4A or SALL4B. Interestingly, all the SALL4Bmice developed MDS-like features at 2 months of age, and nine of them (53%) progressed to AML. In contrast, the SALL4A mice did not exhibit leukemia formation during the test period [59]. These studies suggest that SALL4B, but not SALL4A, has oncogenic activity in inducing leukemogenesis. In mechanism studies, the SALL4 isoforms were found to bind β-catenin protein, and these factors synergistically enhanced the Wnt/β-catenin signaling pathway. As expected, the expression levels of cyclin-D1 and c-Myc, the two known targets of the Wnt/β-catenin pathway, were both increased in the SALL4Bmice bone marrow cells. Interestingly, in a recent study, transgenic activation of the SALL4 target β-catenin in osteoblasts, the HSC/HPC niche, also induced MDS and AML development. Notably, these β-catenin mutated mice were anemic at as early as 2 weeks and died before 6 weeks of age, indicating a severe driving event in leukemogenesis [71]. Further in-depth studies are therefore needed to elucidate whether SALL4B in transgenic mice potentially induces leukemogenesis via activating β-catenin in the osteoblastic niche.

Recently, our group explored SALL4 functions in leukemia pathogenesis induced by MLL-AF9, one of the most common mixed lineage leukemia (MLL)-rearranged (MLL-r) oncoproteins found in leukemia patients which is associated with very poor prognosis [72, 73, 74, 75, 76]. A previous study showed that SALL4 physically interacts with the MLL wild type protein in regulating HOXA9 expression [77]. In this study, our data revealed that loss of SALL4 in MLL-AF9-transformed bone marrow cells largely disrupted their clonogenic ability in methylcellulose-based medium and in liquid culture, induced markable apoptosis and cell cycle arrest at G1. Consistently, conditional disruption of both Sall4alleles in transplanted mice completely blocked leukemia initiation and significantly attenuated pre-existing disease progression [46]. Therefore, these studies suggest that SALL4 is an essential transcriptional regulator in MLL-r leukemogenesis.

4.3. SALL4 regulated pathways in leukemia

Our research group has previously conducted ChIP-on-chip assays with a promyelocytic leukemic cell line NB4 [78]. Analysis of the SALL4-bound genes revealed the most prominent pathways involving WNT/β-catenin, apoptosis, NOTCH signaling, the polycomb complex protein BMI-1, PTEN, and nuclear factor-kB (see Figure 3). When the cells were treated with a SALL4-specific shRNA vector, the expression levels of proapoptotic genes TNF, TP53, PTEN, CARD9, CARD11, ATF3, and LTA were upregulated. In contrast, the expression levels of anti-apoptotic genes such as BCL2, BMI-1, DAD1, TEGT, BIRC7, and BIRC4 (XIAP) are downregulated. In line with the expression studies, reduction of SALL4 also diminished tumorigenicity of leukemic cells in immunodeficient mice. Further, the SALL4 knockdown-induced apoptosis was reversed by ectopic expression BMI-1. In a separate study, SALL4 knockdown in combination with a BCL-2 inhibitor also synergistically increased apoptosis in AML cells. Other studies have reported that SALL4 recruits the nucleosome remodeling and histone deacetylation (NuRD/HDAC) repressive complex to the promoter of PTENand decrease its gene expression [79], while conversely, a SALL4-derived peptide blocking this protein-protein interaction resulted in notable leukemic cell death, and this effect was reversed by treatment of a PTEN inhibitor [80]. In AML differentiation studies, SALL4 expression has also been reported to block all-trans retinoic acid (ATRA)-induced myeloid differentiation in ATRA-sensitive and -resistant AML cells. Further, inhibition of SALL4 and its interacting epigenetic factor LSD1 synergistically promoted ATRA-induced cell differentiation and growth arrest. In mechanistic studies, SALL4 and LSD1 have been found to co-occupy on the ATRA targets RARβ, ID2, and CYP26gene promoters, and cooperatively regulate their expression [81, 82].

Figure 3.

Key signaling pathways bound by SALL4 in NB4 acute promyelocytic and MLL-AF9 transformed leukemic cells.

Recently, our research group also conducted ChIP assays with sequencing (ChIP-Seq) assays with MLL-AF9 transformed murine leukemic cells. This study revealed that SALL4 binds to the key MLL-AF9 target genes Meis1, Hoxa9; MLL-r leukemia related genes Cebpα, Id2, Elf1, Evl, Flt3, Nf1, Tal1, Tcf7l1, Nkx23; the Hox factors Hoxa-9, −10, −11, −13; the Notch ligand Jag2, and Wnt/β-catenin regulator Wnt7b(see Figure 3 and [46]). mRNA microarrays assays following early Sall4deletion identified multiple upregulated genes including cell cycle inhibitors Cdkn1a (p21), Trp53inp1; HSC/HPC colony-forming repressor Slfn2; and hematopoietic differentiation markers Col5a1, Fyb, Irf8and Pira6. In contrast, the TGFβ family genes, Tgfβ2, Tgfβ3, Tgfβr3,and the genes related to chemo-resistance or leukemia aggressiveness, such as Thbs1, Tgm2, and Ambp were downregulated [46, 83]. In comparison with the mRNA expression data, not many of the ChIP-Seq-identified SALL4 targets were associated with early expression changes. This limited overlap has been considered to be related to the length of time of SALL4 inactivation, the presence of other co-regulators in play, and/or the relatively lower number of genes identified in relevant assays. More detailed studies would help to address these issues.

4.4. SALL4 regulates different downstream networks in normal and leukemic cells

In the SALL4-binding genes identified in NB4 leukemia and those in normal CD34+ cells, less than 20% of the targets were found commonly bound by SALL4. This limited overlap mirrors the findings from ESC and XEN cell promoter binding studies, and further indicates that SALL4 functions in a manner specific to cell type or cell context (see Figure 4). Particularly, downregulation of SALL4 expression seems to have an opposite effect on genes involved apoptosis. For example, in leukemic cells, when SALL4 was downregulated along with the apoptotic phenotype, the expression levels of proapoptosis genes TRO and ABL1 increased, and the expression of anti-apoptosis gene BCL2 decreased. While in CD34+ cells, there was no notable apoptosis with SALL4 knockdown, and the expression of BCL2 increased whereas the expression of TRO and ABL1 decreased. This differential regulatory effect by SALL4 should be helpful in developing SALL4-targeted anti-leukemia strategies to spare normal blood cells.

Figure 4.

SALL4 functions in a manner specific to cell type or cell context. Shown are main effects following SALL4 knockdown in indicated cell types.

Advertisement

5. Epigenetic mechanisms involved in SALL4’s regulatory functions

5.1. SALL4 interacts with a variety of epigenetic factors to regulate downstream gene expression

So far the reported SALL4-interacting epigenetic factors (see Figure 5) include: DNA methyltransferases DNMT-1, -3A, -3B, -3 L, methyl-CpG-binding domain 2 protein (MBD2) [84]; NuRD complex that contains histone deacetylases HDAC1/2 [79]; H3K4 methyltransferase MLL1 [77]; H3K79 methyltransferase DOT1L [46]; H3K36 methyltransferase Wolf-Hirschhorn syndrome candidate 1 (WHSC1) [85, 86]; and lysine-specific histone demethylase LSD1/KDM1A [46, 81, 87]. All of these are critical regulators in normal blood development and are frequent targets for dysregulation in hematological malignancies [88, 89, 90], and clinical epigenetic remedies inhibiting such epigenetic factors have been shown effective in treating leukemia [91, 92, 93]. In fact, in MLL-AF9-mediated mouse AML studies, genetic disruption of either SALL4, DNMT1, LSD1, or DOT1L likewise blocked leukemia initiation and delayed disease progression in vivo[94, 95, 96].

Figure 5.

The SALL4-associated epigenetic factors. DNMTs: DNA methyltransferases. HDACs: histone deacetylases. HDMs: histone demethylases. HMTs: histone methyltransferases.

By interacting with specific epigenetic factors, SALL4 expression can affect DNA methylation and histone methylation/acetylation status at genes that control hematopoietic differentiation, apoptosis, tumor induction or suppression. For example, in NB4 AML cells that were transduced with a lentiviral SALL4 vector, there was an overall increased percentage of DNA methylation at various CpG sites of tumor suppression gene PTEN, which co-relates with a downregulated gene transcription [84]. In mouse bone marrow LSK cells, overexpression of SALL4 also induced increased percentage of methylation at the CpG sites of early B-cell factor 1 (Ebf1) promoter, as well as the Sall4gene promoter itself, which facilitates an undifferentiated cellular status [84]. Similarly, the SALL4 overexpression levels significantly affected LSD1 binding and altered H3K4me2 levels at the promoter regions of tumor necrosis factor (Tnf) and differentiation-related genes EBF1, GATA1, RARβ, ID2, and CYP26, which are associated with relevantly altered gene transcription levels [81, 87]. Also, while SALL4 interacts with the NuRD/HDAC1/2 complex to silence PTENpromoter via reduced acetylation of histone H3 at its binding sites, the SALL4-derived peptide blocks this interaction and leads to reactivated PTEN expression. Additionally, in the 32D myeloid progenitor cells following lentiviral SALL4 transduction, the H3K4me3 and H3K79me2/3 levels at Bmi1promoter regions were increased [45]. In MLL-AF9 leukemia studies, the expression levels of SALL4 also affected LSD1 and Dot1l binding and relevant H3K4me3 and H3K79me3 amounts at the promoter regions of Meis1and multiple HOX family genes in bone marrow cells [46, 77, 79].

5.2. SALL4 regulated epigenetic modification programs are cell type-dependent

Consistent with the findings from SALL4 genome-wide promoter binding and relevant expression assays, SALL4-regulated epigenetic modification programs are also strictly dependent on the cellular context. As reported, SALL4-bound genomic loci in murine ESCs are largely enriched for the activating marker H3K4me3, which indicates an association of SALL4 with non-repressed genes. In XEN cells, however, SALL4-binding loci displayed significantly less H3K4me3 enrichment. Instead, most of these regions are either accompanied with H3K27me3 or lacking both H3K4me3 and H3K27me3, the “epi-markers” frequently associated with gene repression [26]. In our MLL-AF9 leukemia model studies, SALL4 has been shown to recruit DOT1L and LSD1 to Meis1and HOX family gene promoters and modulate their H3K79me2/3 and H3K4me3 levels [46]. The previously demonstrated SALL4-MLL interaction may contribute to the observed HEK4me3 changes. However, in some non-MLL-r human AMLs, the DOT1L-regulated H3K79 methylation may not play a role, and it has been reported that administration of DOT1l inhibitors sensitized chemotherapy in MLL-r but not in non-MLL-r AML cells [97]. Further, the DOT1L recruitment to MLL-AF9 has been associated with the level of leukemic transformation [98, 99, 100]. Therefore, one may anticipate that SALL4 differentially interacts with individual epigenetic factors to exerting a disease/subtype–dependent regulatory effect. This concept, if proven true, should further facilitate the development of SALL4-based disease subtype–specific anti-leukemia strategies.

Advertisement

6. Conclusions

Abnormal expression of SALL4 has been frequently detected in different types of human leukemias and associated with disease status and drug treatments. On the other hand, proper manipulation of SALL4 expression might be useful in achieving clinically significant expansion of transplantable human HSCs. Therefore, understanding how SALL4 mechanisms maintain normal HSCs/HPCs vs. leukemic cells will facilitate development of newer, more efficient therapies in clinic.

Advertisement

Acknowledgments

This work was partially supported by American Cancer Society Research Scholar Grant RSG-12-216-01-LIB (to J.Y.).

Advertisement

Conflict of interest

The authors declare that they have no conflicts of interest with the contents of this article.

Advertisement

Acronyms and abbreviations

ESCembryonic stem cell
HSPs/HPCshematopoietic stem/progenitor cells
C2H2-ZFCys2His2 zinc finger
PRCpolycomb-repressive complexes
ChIP-on-chipchromatin immunoprecipitation followed by microarray hybridization
ICMinner cell mass
XENextraembryonic endoderm
iPSCinduced pluripotent stem cell
LSKlineage- Sca-1+ c-kit+
G-CSFgranulocyte-colony stimulating factor
MDSmyelodysplastic syndrome
AMLacute myeloid leukemia
FABthe French-American-British classification
ALK+ ALCLALK positive anaplastic large cell lymphoma
B-ALLB cell acute lymphocytic leukemia
CMLchronic myeloid leukemia
MLL-rmixed lineage leukemia (MLL)-rearranged
NuRD/HDACnucleosome remodeling and histone deacetylation
ATRAall-trans retinoic acid
ChIP-SeqChIP assays with sequencing
MBD2methyl-CpG-binding domain 2 protein
WHSC1Wolf-Hirschhorn syndrome candidate 1
Ebf1early B-cell factor 1

References

  1. 1. Kohlhase J, Schuh R, Dowe G, Kuhnlein RP, Jackle H, Schroeder B, et al. Isolation, characterization, and organ-specific expression of two novel human zinc finger genes related to the drosophila gene Spalt. Genomics. 1996;38(3):291-298
  2. 2. Eildermann K, Aeckerle N, Debowski K, Godmann M, Christiansen H, Heistermann M, et al. Developmental expression of the pluripotency factor Sal-like protein 4 in the monkey, human and mouse testis: Restriction to premeiotic germ cells. Cells, Tissues, Organs. 2012;196(3):206-220. PubMed PMID: 22572102
  3. 3. Sweetman D, Munsterberg A. The vertebrate Spalt genes in development and disease. Developmental Biology. 2006;293(2):285-293. PubMed PMID: 16545361
  4. 4. Yang J, Liao W, Ma Y. Role of SALL4 in hematopoiesis. Current Opinion in Hematology. 2012;19(4):287-291
  5. 5. Kohlhase J, Heinrich M, Schubert L, Liebers M, Kispert A, Laccone F, et al. Okihiro syndrome is caused by SALL4 mutations. Human Molecular Genetics. 2002;11(23):2979-2987. PubMed PMID: 12393809
  6. 6. Kohlhase J. SALL4-related disorders. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mefford HC, et al., editors. Gene Reviews. Seattle, WA; 1993. GeneReviews® [Internet]. Available from:https://www.ncbi.nlm.nih.gov/books/NBK1373/
  7. 7. Tatetsu H, Kong NR, Chong G, Amabile G, Tenen DG, Chai L. SALL4, the missing link between stem cells, development and cancer. Gene. 2016;584(2):111-119
  8. 8. Xiong J. SALL4: Engine of cell Stemness. Current Gene Therapy. 2014;14(5):400-411. PubMed PMID: 25174577
  9. 9. Al-Baradie R, Yamada K, St Hilaire C, Chan WM, Andrews C, McIntosh N, et al. Duane radial ray syndrome (Okihiro syndrome) maps to 20q13 and results from mutations in SALL4, a new member of the SAL family. American Journal of Human Genetics. 2002;71(5):1195-1199
  10. 10. Kohlhase J, Schubert L, Liebers M, Rauch A, Becker K, Mohammed SN, et al. Mutations at the SALL4 locus on chromosome 20 result in a range of clinically overlapping phenotypes, including Okihiro syndrome, Holt-Oram syndrome, acro-renal-ocular syndrome, and patients previously reported to represent thalidomide embryopathy. Journal of Medical Genetics. 2003;40(7):473-478. PubMed PMID: 12843316; PubMed Central PMCID: PMCPMC1735528
  11. 11. Paradisi I, Arias S. IVIC syndrome is caused by a c.2607delA mutation in the SALL4 locus. American Journal of Medical Genetics Part A. 2007;143(4):326-332. PubMed PMID: 17256792
  12. 12. Zhang X, Yuan X, Zhu W, Qian H, Xu W. SALL4: An emerging cancer biomarker and target. Cancer Letters. 2015;357(1):55-62. PubMed PMID: 25444934
  13. 13. Wang F, Zhao W, Kong N, Cui W, Chai L. The next new target in leukemia: The embryonic stem cell gene SALL4. Mol Cell Oncol. 2014;1(4):e969169. PubMed PMID: 25977939; PubMed Central PMCID: PMCPMC4428154
  14. 14. Zhang J, Tam WL, Tong GQ, Wu Q, Chan HY, Soh BS, et al. Sall4 modulates embryonic stem cell pluripotency and early embryonic development by the transcriptional regulation of Pou5f1. Nature Cell Biology. 2006;8(10):1114-1123
  15. 15. Yang J, Gao C, Chai L, Ma Y. A novel SALL4/OCT4 transcriptional feedback network for pluripotency of embryonic stem cells. PLoS One. 2010;5(5):e10766. PubMed PMID: 20505821; PubMed Central PMCID: PMC2874005
  16. 16. Nosi U, Lanner F, Huang T, Cox B. Overexpression of trophoblast stem cell-enriched microRNAs promotes trophoblast fate in embryonic stem cells. Cell Reports. 2017;19(6):1101-1109. PubMed PMID: 28494860
  17. 17. Miller A, Gharbi S, Etienne-Dumeau C, Nishinakamura R, Hendrich B. Transcriptional control by Sall4 in blastocysts facilitates lineage commitment of inner cell mass cells. bioRxiv. 2017
  18. 18. Yang J, Chai L, Fowles TC, Alipio Z, Xu D, Fink LM, et al. Genome-wide analysis reveals Sall4 to be a major regulator of pluripotency in murine-embryonic stem cells. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(50):19756-19761. PubMed PMID: 19060217; PubMed Central PMCID: PMC2604985
  19. 19. Abboud N, Moore-Morris T, Hiriart E, Yang H, Bezerra H, Gualazzi MG, et al. A cohesin-OCT4 complex mediates Sox enhancers to prime an early embryonic lineage. Nature Communications. 2015;6:6749. PubMed PMID: 25851587; PubMed Central PMCID: PMCPMC5531045
  20. 20. Xu K, Chen X, Yang H, Xu Y, He Y, Wang C, et al. Maternal Sall4 is indispensable for epigenetic maturation of mouse oocytes. The Journal of Biological Chemistry. 2017;292(5):1798-1807. PubMed PMID: 28031467; PubMed Central PMCID: PMCPMC5290953
  21. 21. Sakaki-Yumoto M, Kobayashi C, Sato A, Fujimura S, Matsumoto Y, Takasato M, et al. The murine homolog of SALL4, a causative gene in Okihiro syndrome, is essential for embryonic stem cell proliferation, and cooperates with Sall1 in anorectal, heart, brain and kidney development. Development. 2006;133(15):3005-3013. PubMed PMID: 16790473
  22. 22. Elling U, Klasen C, Eisenberger T, Anlag K, Treier M. Murine inner cell mass-derived lineages depend on Sall4 function. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(44):16319-16324. PubMed PMID: 17060609; PubMed Central PMCID: PMCPMC1637580
  23. 23. Warren M, Wang W, Spiden S, Chen-Murchie D, Tannahill D, Steel KP, et al. A Sall4 mutant mouse model useful for studying the role of Sall4 in early embryonic development and organogenesis. Genesis. 2007;45(1):51-58. PubMed PMID: 17216607; PubMed Central PMCID: PMCPMC2593393
  24. 24. Harvey SA, Logan MP. Sall4 acts downstream of tbx5 and is required for pectoral fin outgrowth. Development. 2006;133(6):1165-1173. PubMed PMID: 16501170
  25. 25. Koshiba-Takeuchi K, Takeuchi JK, Arruda EP, Kathiriya IS, Mo R, Hui CC, et al. Cooperative and antagonistic interactions between Sall4 and Tbx5 pattern the mouse limb and heart. Nature Genetics. 2006;38(2):175-183. PubMed PMID: 16380715
  26. 26. Lim CY, Tam WL, Zhang J, Ang HS, Jia H, Lipovich L, et al. Sall4 regulates distinct transcription circuitries in different blastocyst-derived stem cell lineages. Cell Stem Cell. 2008;3(5):543-554
  27. 27. Oikawa T, Kamiya A, Kakinuma S, Zeniya M, Nishinakamura R, Tajiri H, et al. Sall4 regulates cell fate decision in fetal hepatic stem/progenitor cells. Gastroenterology. 2009;136(3):1000-1011. PubMed PMID: 19185577
  28. 28. Bohm J, Heinritz W, Craig A, Vujic M, Ekman-Joelsson BM, Kohlhase J, et al. Functional analysis of the novel TBX5 c.1333delC mutation resulting in an extended TBX5 protein. BMC Medical Genetics. 2008;9:88. PubMed PMID: 18828908; PubMed Central PMCID: PMCPMC2567295
  29. 29. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663-676. PubMed PMID: 16904174
  30. 30. Tsubooka N, Ichisaka T, Okita K, Takahashi K, Nakagawa M, Yamanaka S. Roles of Sall4 in the generation of pluripotent stem cells from blastocysts and fibroblasts. Genes to Cells. 2009;14(6):683-694. PubMed PMID: 19476507
  31. 31. Wong CC, Gaspar-Maia A, Ramalho-Santos M, Reijo Pera RA. High-efficiency stem cell fusion-mediated assay reveals Sall4 as an enhancer of reprogramming. PLoS One. 2008;3(4):e1955. PubMed PMID: 18414659; PubMed Central PMCID: PMCPMC2278370
  32. 32. Shu J, Zhang K, Zhang M, Yao A, Shao S, Du F, et al. GATA family members as inducers for cellular reprogramming to pluripotency. Cell Research. 2015;25(2):169-180. PubMed PMID: 25591928; PubMed Central PMCID: PMCPMC4650575
  33. 33. Buganim Y, Markoulaki S, van Wietmarschen N, Hoke H, Wu T, Ganz K, et al. The developmental potential of iPSCs is greatly influenced by reprogramming factor selection. Cell Stem Cell. 2014;15(3):295-309. PubMed PMID: 25192464; PubMed Central PMCID: PMCPMC4170792
  34. 34. Mansour AA, Gafni O, Weinberger L, Zviran A, Ayyash M, Rais Y, et al. The H3K27 demethylase Utx regulates somatic and germ cell epigenetic reprogramming. Nature. 2012;488(7411):409-413. PubMed PMID: 22801502
  35. 35. Pacini S, Carnicelli V, Trombi L, Montali M, Fazzi R, Lazzarini E, et al. Constitutive expression of pluripotency-associated genes in mesodermal progenitor cells (MPCs). PLoS One. 2010;5(3):e9861. PubMed PMID: 20360837; PubMed Central PMCID: PMCPMC2845604
  36. 36. Jia G, Preussner J, Guenther S, Yuan X, Yekelchyk M, Kuenne C, et al. Single cell RNA-seq and ATAC-seq indicate critical roles of Isl1 and Nkx2-5 for cardiac progenitor cell transition states and lineage settlement. bioRxiv. 2017
  37. 37. Gao C, Kong NR, Li A, Tatetu H, Ueno S, Yang Y, et al. SALL4 is a key transcription regulator in normal human hematopoiesis. Transfusion. 2013;53(5):1037-1049. PubMed PMID: 22934838; PubMed Central PMCID: PMC3653586
  38. 38. Rao S, Zhen S, Roumiantsev S, McDonald LT, Yuan GC, Orkin SH. Differential roles of Sall4 isoforms in embryonic stem cell pluripotency. Molecular and Cellular Biology. 2010;30(22):5364-5380. PubMed PMID: 20837710; PubMed Central PMCID: PMCPMC2976381
  39. 39. Yang J, Aguila JR, Alipio Z, Lai R, Fink LM, Ma Y. Enhanced self-renewal of hematopoietic stem/progenitor cells mediated by the stem cell gene Sall4. Journal of Hematology & Oncology. 2011;4:38. PubMed PMID: 21943195; PubMed Central PMCID: PMC3184628
  40. 40. Aguila JR, Liao W, Yang J, Avila C, Hagag N, Senzel L, et al. SALL4 is a robust stimulator for the expansion of hematopoietic stem cells. Blood. 2011;118(3):576-585. PubMed PMID: 21602528; PubMed Central PMCID: PMC3142902
  41. 41. Liao W, Aguila JR, Yao Y, Yang J, Zieve G, Jiang Y, et al. Enhancing bone marrow regeneration by SALL4 protein. Journal of Hematology & Oncology. 2013;6:84. PubMed PMID: 24283261; PubMed Central PMCID: PMCPMC3882884
  42. 42. Mossahebi-Mohammadi M, Atashi A, Kaviani S, Soleimani M. Efficient expansion of SALL4-transduced umbilical cord blood derived CD133+hematopoietic stem cells. Acta Medica Iranica. 2017;55(5):290-296. PubMed PMID: 28724268
  43. 43. Tatetsu H, Wang F, Gao C, Ueno S, Tian X, Armant M, et al. SALL4 is a key factor in HDAC inhibitor mediated ex vivo expansion of human peripheral blood mobilized stem/progenitor CD34+CD90+ cells. Blood. 2014;124(21):1566
  44. 44. Akhavan Rahnama M, Movassaghpour AA, Soleimani M, Atashi A, Anbarlou A, Shams AK. MicroRNA-15b target Sall4 and diminish in vitro UCB-derived HSCs expansion. EXCLI Journal. 2015;14:601-610. PubMed PMID: 26648817; PubMed Central PMCID: PMCPMC4669904
  45. 45. Yang J, Chai L, Liu F, Fink LM, Lin P, Silberstein LE, et al. Bmi-1 is a target gene for SALL4 in hematopoietic and leukemic cells. Proceedings of the National Academy of Sciences of the United States of America. 2007;104(25):10494-10499. PubMed PMID: 17557835; PubMed Central PMCID: PMC1965541
  46. 46. Yang L, Liu L, Gao H, Pinnamaneni JP, Sanagasetti D, Singh VP, et al. The stem cell factor SALL4 is an essential transcriptional regulator in mixed lineage leukemia-rearranged leukemogenesis. Journal of Hematology & Oncology. 2017;10(1):159
  47. 47. Rossi L, Lin KK, Boles NC, Yang L, King KY, Jeong M, et al. Less is more: Unveiling the functional core of hematopoietic stem cells through knockout mice. Cell Stem Cell. 2012;11(3):302-317. PubMed PMID: 22958929; PubMed Central PMCID: PMCPMC3461270
  48. 48. Damnernsawad A, Kong G, Wen Z, Liu Y, Rajagopalan A, You X, et al. Kras is required for adult hematopoiesis. Stem Cells. 2016;34(7):1859-1871. PubMed PMID: 26972179; PubMed Central PMCID: PMCPMC5358545
  49. 49. Oikawa T, Kamiya A, Zeniya M, Chikada H, Hyuck AD, Yamazaki Y, et al. Sal-like protein 4 (SALL4), a stem cell biomarker in liver cancers. Hepatology. 2013;57(4):1469-1483. PubMed PMID: 23175232
  50. 50. Ushiku T, Shinozaki A, Shibahara J, Iwasaki Y, Tateishi Y, Funata N, et al. SALL4 represents fetal gut differentiation of gastric cancer, and is diagnostically useful in distinguishing hepatoid gastric carcinoma from hepatocellular carcinoma. The American Journal of Surgical Pathology. 2010;34(4):533-540. PubMed PMID: 20182341
  51. 51. Kobayashi D, Kuribayashi K, Tanaka M, Watanabe N. Overexpression of SALL4 in lung cancer and its importance in cell proliferation. Oncology Reports. 2011;26(4):965-970. PubMed PMID: 21725617
  52. 52. Kobayashi D, Kuribayshi K, Tanaka M, Watanabe N. SALL4 is essential for cancer cell proliferation and is overexpressed at early clinical stages in breast cancer. International Journal of Oncology. 2011;38(4):933-939. PubMed PMID: 21274508
  53. 53. Ardalan Khales S, Abbaszadegan MR, Abdollahi A, Raeisossadati R, Tousi MF, Forghanifard MM. SALL4 as a new biomarker for early colorectal cancers. Journal of Cancer Research and Clinical Oncology. 2014. PubMed PMID: 25156818
  54. 54. Zhang L, Yan Y, Jiang Y, Cui Y, Zou Y, Qian J, et al. The expression of SALL4 in patients with gliomas: High level of SALL4 expression is correlated with poor outcome. Journal of Neuro-Oncology. 2015;121(2):261-268. PubMed PMID: 25359397
  55. 55. Miettinen M, Wang Z, McCue PA, Sarlomo-Rikala M, Rys J, Biernat W, et al. SALL4 expression in germ cell and non-germ cell Tumors: A systematic Immunohistochemical study of 3215 cases. The American Journal of Surgical Pathology. 2014;38(3):410-420. PubMed PMID: 24525512
  56. 56. Mei K, Liu A, Allan RW, Wang P, Lane Z, Abel TW, et al. Diagnostic utility of SALL4 in primary germ cell tumors of the central nervous system: A study of 77 cases. Modern Pathology. 2009;22(12):1628-1636. PubMed PMID: 19820689
  57. 57. Cao D, Guo S, Allan RW, Molberg KH, Peng Y. SALL4 is a novel sensitive and specific marker of ovarian primitive germ cell tumors and is particularly useful in distinguishing yolk sac tumor from clear cell carcinoma. The American Journal of Surgical Pathology. 2009;33(6):894-904. PubMed PMID: 19295406
  58. 58. Wang F, Guo Y, Chen Q, Yang Z, Ning N, Zhang Y, et al. Stem cell factor SALL4, a potential prognostic marker for myelodysplastic syndromes. Journal of Hematology & Oncology. 2013;6(1):73. PubMed PMID: 24283704; PubMed Central PMCID: PMC3856454
  59. 59. Ma Y, Cui W, Yang J, Qu J, Di C, Amin HM, et al. SALL4, a novel oncogene, is constitutively expressed in human acute myeloid leukemia (AML) and induces AML in transgenic mice. Blood. 2006;108:2726-2735
  60. 60. Abo-Elwafa H, Aziz S, Salah M, Sedek O. The SALL4 gene in acute leukemias. The Egyptian Journal of Haematology. 2015;40(3):121-129
  61. 61. Shen Q, Liu S, Hu J, Chen S, Yang L, Li B, et al. The differential expression pattern of the BMI-1, SALL4 and ABCA3 genes in myeloid leukemia. Cancer Cell International. 2012;12(1):42. PubMed PMID: 23067006; PubMed Central PMCID: PMCPMC3538712
  62. 62. Jeong HW, Cui W, Yang Y, Lu J, He J, Li A, et al. SALL4, a stem cell factor, affects the side population by regulation of the ATP-binding cassette drug transport genes. PLoS One. 2011;6(4):e18372. PubMed PMID: 21526180; PubMed Central PMCID: PMC3079717
  63. 63. Wang F, Gao C, Lu J, Tatetsu H, Williams DA, Muller LU, et al. Leukemic survival factor SALL4 contributes to defective DNA damage repair. Oncogene. 2016;35(47):6087-6095. PubMed PMID: 27132514; PubMed Central PMCID: PMCPMC5093088
  64. 64. Chen Q, Qian J, Lin J, Yang J, Li Y, Wang CZ, et al. Expression of SALL4 gene in patients with acute and chronic myeloid leukemia. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2013;21(2):315-319. PubMed PMID: 23628023
  65. 65. Milanovich S, Peterson J, Allred J, Stelloh C, Rajasekaran K, Fisher J, et al. Sall4 overexpression blocks murine hematopoiesis in a dose-dependent manner. Experimental Hematology. 2015;43(1):53-64 e1-8. PubMed PMID: 25246269; PubMed Central PMCID: PMCPMC4268405
  66. 66. Wang P, Zhang JD, Wu F, Ye X, Sharon D, Hitt M, et al. The expression and oncogenic effects of the embryonic stem cell marker SALL4 in ALK-positive anaplastic large cell lymphoma. Cellular Signalling. 2012;24(10):1955-1963. PubMed PMID: 22743134
  67. 67. Ueno S, Lu J, He J, Li A, Zhang X, Ritz J, et al. Aberrant expression of SALL4 in acute B cell lymphoblastic leukemia: Mechanism, function, and implication for a potential novel therapeutic target. Experimental Hematology. 2014;42(4):307-316 e8. PubMed PMID: 24463278; PubMed Central PMCID: PMC4135469
  68. 68. Cui W, Kong NR, Ma Y, Amin HM, Lai R, Chai L. Differential expression of the novel oncogene, SALL4, in lymphoma, plasma cell myeloma, and acute lymphoblastic leukemia. Modern Pathology. 2006;19(12):1585-1592. PubMed PMID: 16998462
  69. 69. Lu J, Ma Y, Kong N, Alipio Z, Gao C, Krause DS, et al. Dissecting the role of SALL4, a newly identified stem cell factor, in chronic myelogenous leukemia. Leukemia. 2011;25(7):1211-1213. PubMed PMID: 21468036; PubMed Central PMCID: PMC3675449
  70. 70. Hupfeld T, Chapuy B, Schrader V, Beutler M, Veltkamp C, Koch R, et al. Tyrosinekinase inhibition facilitates cooperation of transcription factor SALL4 and ABC transporter A3 towards intrinsic CML cell drug resistance. British Journal of Haematology. 2013;161(2):204-213. PubMed PMID: 23432194
  71. 71. Kode A, Manavalan JS, Mosialou I, Bhagat G, Rathinam CV, Luo N, et al. Leukaemogenesis induced by an activating beta-catenin mutation in osteoblasts. Nature. 2014;506(7487):240-244. PubMed PMID: 24429522; PubMed Central PMCID: PMCPMC4116754
  72. 72. Prange KHM, Mandoli A, Kuznetsova T, Wang SY, Sotoca AM, Marneth AE, et al. MLL-AF9 and MLL-AF4 on cofusion proteins bind a distinct enhancer repertoire and target the RUNX1 program in 11q23 acute myeloid leukemia. Oncogene. 2017;36(23):3346-3356. PubMed PMID: 28114278; PubMed Central PMCID: PMCPMC547456r5
  73. 73. Winters AC, Bernt KM. MLL-rearranged leukemias—An update on science and clinical approaches. Frontiers in Pediatrics. 2017;5:4. PubMed PMID: 28232907; PubMed Central PMCID: PMCPMCr5299633
  74. 74. Zhu N, Chen M, Eng R, DeJong J, Sinha AU, Rahnamay NF, et al. MLL-AF9- and HOXA9-mediated acute myeloid leukemia stem cell self-renewal requires JMJD1C. The Journal of Clinical Investigation. 2016;126(3):997-1011. PubMed PMID: 26878175
  75. 75. Marschalek R. MLL leukemia and future treatment strategies. Archiv der Pharmazie (Weinheim). 2015;348(4):221-228. PubMed PMID: 25740345
  76. 76. de Boer J, Walf-Vorderwulbecke V, Williams O. In focus: MLL-rearranged leukemia. Leukemia. 2013;27(6):1224-1228. PubMed PMID: 23515098
  77. 77. Li A, Yang Y, Gao C, Lu J, Jeong HW, Liu BH, et al. A SALL4/MLL/HOXA9 pathway in murine and human myeloid leukemogenesis. The Journal of Clinical Investigation. 2013;123(10):4195-4207. PubMed PMID: 24051379; PubMed Central PMCID: PMC3r784519
  78. 78. Yang J, Chai L, Gao C, Fowles TC, Alipio Z, Dang H, et al. SALL4 is a key regulator of survival and apoptosis in human leukemic cells. Blood. 2008;112(3):805-813
  79. 79. Lu J, Jeong HW, Kong N, Yang Y, Carroll J, Luo HR, et al. Stem cell factor SALL4 represses the transcriptions of PTEN and SALL1 through an epigenetic repressor complex. PLoS One. 2009;4(5):e5577. PubMed PMID: 19440552; PubMed Central PMCID: PMC2679146
  80. 80. Gao C, Dimitrov T, Yong KJ, Tatetsu H, Jeong HW, Luo HR, et al. Targeting transcription factor SALL4 in acute myeloid leukemia by interrupting its interaction with an epigenetic complex. Blood. 2013;121(8):1413-1421. PubMed PMID: 23287862; PubMed Central PMCID: PMC3578956
  81. 81. Liu L, Liu L, Leung E, Cooney AJ, Chen C, Rosengart TK, et al. Knockdown of SALL4 enhances all-trans retinoic acid-induced cellular differentiation in acute myeloid leukemia cells. The Journal of Biological Chemistry. 2015;290(17):10599-10609. PubMed PMID: 25737450
  82. 82. Gao C, Kong NR, Chai L. The role of stem cell factor SALL4 in leukemogenesis. Critical Reviews in Oncogenesis. 2011;16(1-2):117-127. PubMed PMID: 22150312; PubMed Central PMCID: PMCPMC3238789
  83. 83. Zhang W, Xia X, Reisenauer MR, Rieg T, Lang F, Kuhl D, et al. Aldosterone-induced Sgk1 relieves Dot1a-Af9-mediated transcriptional repression of epithelial Na+ channel alpha. The Journal of Clinical Investigation. 2007;117(3):773-783
  84. 84. Yang J, Corsello TR, Ma Y. Stem cell gene SALL4 suppresses transcription through recruitment of DNA methyltransferases. The Journal of Biological Chemistry. 2012;287(3):1996-2005. PubMed PMID: 22128185; PubMed Central PMCID: PMC3265879
  85. 85. Campos-Sanchez E, Deleyto-Seldas N, Dominguez V, Carrillo-de-Santa-Pau E, Ura K, Rocha PP, et al. Wolf-Hirschhorn syndrome candidate 1 is necessary for correct hematopoietic and B cell development. Cell Reports. 2017;19(8):1586-1601. PubMed PMID: 28538178; PubMed Central PMCID: PMCPMC5510986
  86. 86. Nimura K, Ura K, Shiratori H, Ikawa M, Okabe M, Schwartz RJ, et al. A histone H3 lysine 36 trimethyltransferase links Nkx2-5 to Wolf-Hirschhorn syndrome. Nature. 2009;460(7252):287-291. PubMed PMID: 19483677
  87. 87. Liu L, Souto J, Liao W, Jiang Y, Li Y, Nishinakamura R, et al. Histone lysine-specific demethylase 1 (LSD1) protein is involved in Sal-like protein 4 (SALL4)-mediated transcriptional repression in hematopoietic stem cells. The Journal of Biological Chemistry. 2013;288(48):34719-34728
  88. 88. Rice KL, Hormaeche I, Licht JD. Epigenetic regulation of normal and malignant hematopoiesis. Oncogene. 2007;26(47):6697-6714. PubMed PMID: 17934479
  89. 89. Goyama S, Kitamura T. Epigenetics in normal and malignant hematopoiesis: An overview and update 2017. Cancer Science. 2017;108(4):553-562. PubMed PMID: 28100030; PubMed Central PMCID: PMCPMC5406607
  90. 90. Ding LW, Sun QY, Tan KT, Chien W, Mayakonda A, Yeoh AEJ, et al. Mutational landscape of pediatric acute lymphoblastic leukemia. Cancer Research. 2017;77(2):390-400. PubMed PMID: 27872090; PubMed Central PMCID: PMCPMC5243866
  91. 91. Wouters BJ, Delwel R. Epigenetics and approaches to targeted epigenetic therapy in acute myeloid leukemia. Blood. 2016;127(1):42-52. PubMed PMID: 26660432
  92. 92. Gallipoli P, Giotopoulos G, Huntly BJ. Epigenetic regulators as promising therapeutic targets in acute myeloid leukemia. Therapeutic Advances in Hematology. 2015;6(3):103-119. PubMed PMID: 26137202; PubMed Central PMCID: PMCPMC4480521
  93. 93. Bernt KM, Armstrong SA. Targeting epigenetic programs in MLL-rearranged leukemias. Hematology. 2011;2011:354-360. PubMed PMID: 22160057
  94. 94. Trowbridge JJ, Sinha AU, Zhu N, Li M, Armstrong SA, Orkin SH. Haploinsufficiency of Dnmt1 impairs leukemia stem cell function through derepression of bivalent chromatin domains. Genes & Development. 2012;26(4):344-349. PubMed PMID: 22345515; PubMed Central PMCID: PMCPMC3289882
  95. 95. Kuntimaddi A, Achille NJ, Thorpe J, Lokken AA, Singh R, Hemenway CS, et al. Degree of recruitment of DOT1L to MLL-AF9 defines level of H3K79 di- and tri-methylation on target genes and transformation potential. Cell Reports. 2015;11(5):808-820. PubMed PMID: 25921540; PubMed Central PMCID: PMCPMC4426023
  96. 96. Harris WJ, Huang X, Lynch JT, Spencer GJ, Hitchin JR, Li Y, et al. The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells. Cancer Cell. 2012;21(4):473-487. PubMed PMID: 22464800
  97. 97. Liu W, Deng L, Song Y, Redell M. DOT1L inhibition sensitizes MLL-rearranged AML to chemotherapy. PLoS One. 2014;9(5):e98270. PubMed PMID: 24858818; PubMed Central PMCID: PMCPMC4032273
  98. 98. Bernt KM, Zhu N, Sinha AU, Vempati S, Faber J, Krivtsov AV, et al. MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L. Cancer Cell. 2011;20(1):66-78. PubMed PMID: 21741597; PubMed Central PMCID: PMCPMC3329803
  99. 99. Bernt KM, Armstrong SA. A role for DOT1L in MLL-rearranged leukemias. Epigenomics. 2011;3(6):667-670. PubMed PMID: 22126283
  100. 100. Chen CW, Armstrong SA. Targeting DOT1L and HOX gene expression in MLL-rearranged leukemia and beyond. Experimental Hematology. 2015;43(8):673-684. PubMed PMID: 26118503; PubMed Central PMCID: PMCPMC4540610

Written By

Jianchang Yang

Submitted: November 13th, 2017 Reviewed: March 13th, 2018 Published: November 5th, 2018