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Keywords:

  • Transcription factors;
  • Acute lymphocytic leukemia;
  • Adult hematopoietic stem cells;
  • Megakaryocyte;
  • Hemangioblast;
  • Erythroid

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. AN ONLY CHILD: SCL IN HEMATOPOIETIC DEVELOPMENT
  5. THE FORGOTTEN CHILD: LYL1 IN HEMATOPOIETIC DEVELOPMENT
  6. BLOOD BROTHERS: SCL AND LYL1 IN ADULT HSCS
  7. SIBLING RIVALRY: SCL AND LYL1 IN ERYTHROID AND MEGAKARYOCYTIC LINEAGES
  8. THE STOLEN CHILDREN: SCL AND LYL1 IN T-ALL
  9. THE FUTURE GENERATION
  10. DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
  11. REFERENCES

The basic helix-loop-helix (bHLH) proteins are a large family of transcription factors that regulate the formation and fate of tissue stem cells. In hematopoiesis, the two major bHLH factors are stem cell leukemia (SCL) and lymphoblastic leukemia-derived sequence 1 (LYL1), both identified more than 20 years ago in chromosomal translocations occurring in T-cell acute lymphoblastic leukemia. SCL was termed the master regulator of hematopoiesis following the observation that SCL knockout mice die from complete lack of blood formation. However, once established, SCL is no longer required for maintenance of hematopoiesis. Pull-down experiments together with add-back experiments in SCL-null embryonic stem cells and generation of mice carrying a germline DNA binding mutation of SCL demonstrates that most of SCL function is mediated through the formation of a large DNA binding multiprotein complex with both repressor and activator potential. Recent genome-wide binding studies in a hematopoietic stem progenitor cell line suggest that SCL and LYL1 preferentially bind target DNA sequences as components of a heptad of transcription factors. LYL1, a paralog of SCL has been the forgotten sibling until recent mouse studies demonstrated that LYL1 replaced the function of SCL in adult hematopoiesis. Why LYL1 can replace the function of SCL for the maintenance but not formation of hematopoiesis remains a fundamental question. This review will compare and contrast the roles of these two transcription factors in hematopoiesis focusing on recent functional and genome-wide binding studies. STEM CELLS2012;30:1053–1058


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. AN ONLY CHILD: SCL IN HEMATOPOIETIC DEVELOPMENT
  5. THE FORGOTTEN CHILD: LYL1 IN HEMATOPOIETIC DEVELOPMENT
  6. BLOOD BROTHERS: SCL AND LYL1 IN ADULT HSCS
  7. SIBLING RIVALRY: SCL AND LYL1 IN ERYTHROID AND MEGAKARYOCYTIC LINEAGES
  8. THE STOLEN CHILDREN: SCL AND LYL1 IN T-ALL
  9. THE FUTURE GENERATION
  10. DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
  11. REFERENCES

The fundamentals that underlie blood cell formation in the embryo and maintenance in the adult have been mapped by research efforts that span many decades. The vertebrate hematopoietic system is highly conserved across evolution, as are the expression patterns and functions of its key regulatory genes. The basic helix-loop-helix (bHLH) proteins are an ancient family of transcription factors that regulate cell identity and tissue development. The bHLH domain, common to all bHLH transcription factors, is divided into two functional regions: a basic region for DNA binding and an HLH region for protein-protein interactions. Tissue-specific bHLH factors usually heterodimerize with ubiquitous E-proteins to regulate transcription of target genes by binding the E-box consensus sequence (CANNTG). T-cell acute lymphocytic leukemia 1, hitherto referred to as stem cell leukemia (SCL), and lymphoblastic leukemia-derived sequence 1 (LYL1) are the major hematopoietic-restricted bHLH factors, both cloned from chromosomal translocations occurring in patients with T-cell acute lymphoblastic leukemia (T-ALL). A detailed review of the role of SCL in hematopoiesis and leukemia was published more than 7 years ago [1]. This review will compare and contrast the roles of SCL and LYL1 in hematopoiesis, focusing on recent functional and genome-wide binding studies.

AN ONLY CHILD: SCL IN HEMATOPOIETIC DEVELOPMENT

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. AN ONLY CHILD: SCL IN HEMATOPOIETIC DEVELOPMENT
  5. THE FORGOTTEN CHILD: LYL1 IN HEMATOPOIETIC DEVELOPMENT
  6. BLOOD BROTHERS: SCL AND LYL1 IN ADULT HSCS
  7. SIBLING RIVALRY: SCL AND LYL1 IN ERYTHROID AND MEGAKARYOCYTIC LINEAGES
  8. THE STOLEN CHILDREN: SCL AND LYL1 IN T-ALL
  9. THE FUTURE GENERATION
  10. DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
  11. REFERENCES

SCL knockout (KO) mice die by embryonic day 9.5 with a complete absence of all hematopoietic cells but are able to generate endothelial cells. SCL is expressed in the hemangioblast, a mesodermal progenitor with endothelial and hematopoietic potential derived during midlate streak gastrulation [2]. While SCL is dispensable for the formation of the hemangioblast, time-lapse photography of hematopoietic development from embryonic stem cells (ESCs) has demonstrated that SCL is critical for the generation of TIE2+c-KIT+CD41 hemogenic intermediates, which generate CD41+ primitive and definitive hematopoiesis [3] (Fig. 1A). Target genes for SCL have been identified by ChIP-seq using hematopoietic progenitor cells and fetal liver cells (see later), but this may not reflect those required for the generation of hemogenic endothelium. RUNX1 is a likely target gene for the formation of definitive hematopoiesis, with SCL binding to the RUNX1 intron 1 + 23 enhancer in the aorta-gonad-mesonephros (AGM) and fetal liver [4]. However, RUNX1 is not required for primitive hematopoiesis and therefore is not a critical target gene of SCL in primitive hematopoiesis.

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Figure 1. Functional roles of stem cell leukemia (SCL) and lymphoblastic leukemia-derived sequence 1 (LYL1) in hematopoiesis. (A): SCL complex is essential for the formation of primitive and definitive hematopoiesis from mesodermal hemangioblast. This does not require DNA binding by SCL (designated by the light blue shading). The DNA binding proteins of the SCL complex (designated by the green oval) in mesodermal hemangioblasts are unknown. LYL1 is unable to replace the function of SCL, presumably due to its distinct N or C termini. (B): Either SCL or LYL1 is sufficient for maintenance and lineage commitment of adult HSCs. DNA binding by SCL (and presumably LYL1) is not required. Preferential DNA binding motifs identified by ChIP-seq in progenitors cells are shown. SCL is required to prevent abnormal lineage commitment of MEPs to MCPs. (C): SCL is required for growth of erythroid (BFU-e) and megakaryocyte (MkP) progenitors by a DNA binding-independent mechanism. In early erythroid cells, the SCL complex includes Gata2 and corepressors such as Eto2. In megakaryocytes, the SCL complex is distinct with binding preference for Runx, Gata1/2, and Fli1. In late erythroid maturation, DNA binding by SCL is important (designated by dark blue shading) and the SCL complex shifts to an activator complex with Gata1. LYL1 is most important for later erythroid maturation. (D): SCL or LYL1 promote aberrant self-renewal of double negative (DN)3 thymocytes in a complex that binds similar motifs to that seen in progenitor cells. In B-cell development, LYL1 promotes and SCL inhibits the formation of pre-B cells from pro-B cells. Abbreviations: BFU-e, blast forming units-erythroid; HSC, hematopoietic stem cell; MCP, mast cell progenitor; MEP, megakaryocyte erythroid progenitor; T-ALL, T-cell acute lymphoblastic leukemia.

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Studies using SCL KO ESCs have shown that the HLH domain of SCL is essential and sufficient for hematopoietic development [5]. Surprisingly, direct DNA binding is not required for in vitro or in vivo hematopoietic development, which indicates that SCL functions in this context through other DNA binding proteins [5, 6]. Central to SCL function in hematopoietic development is the ability to bind to the LIM only protein LMO2 through conserved residues in the loop and helix 2 [5, 7, 8]. Accordingly, mouse KOs of LMO2 and its binding partner LDB1 have complete failure of hematopoiesis like SCL KO mice [9, 10].

To understand what regulates the master regulator of hematopoiesis, Green and colleagues have extensively mapped the enhancer elements of the SCL locus using transgenic reporter assays (Fig. 2A). The two recognized promoters (promoter 1a and 1b) in alternate 5′ exons (1a and 1b) have no hematopoietic activity in transgenic assays [11]. Three distal elements (−4, +19, and +40 kb in relation to exon 1a) drive distinct hematopoietic and endothelial expression of SCL. The −4 element directs reporter expression predominantly to endothelial cells [12], the +19 element targets all hematopoietic stem cells (HSCs), and progenitor cells as well as endothelium [12–14] and the +40 element targets primitive and definitive erythroid cells [15]. Although expression of SCL under control of the +19 enhancer rescued blood progenitor formation in SCL KO embryos [13], disruption of this element within the endogenous SCL locus using a KO approach does not disrupt the formation of hematopoietic cells [16], highlighting the functional redundancy of these multiple hematopoietic enhancers.

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Figure 2. Structure and sequence conservation of the stem cell leukemia (SCL) and lymphoblastic leukemia-derived sequence 1 (LYL1) loci. (A): Vista conservation plots of mouse (M) and human (H) DNA sequence alignments of the SCL (Tal1) locus and flanking genes. Exons are represented as boxes with conserved (i.e., >70%) translated exons colored in dark blue, untranslated exons in cyan, and conserved noncoding regions in pink. The brown arrowheads mark locations of murine SCL regulatory elements. (B): Vista conservation plots of mouse (M) and human (H) DNA sequence alignments of the LYL1 locus and flanking genes. The proximal promoter (P) contains regulatory sequences that are sufficient to target reporter expression to LYL1 expressing tissues in the developing embryo.

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Characterization of core transcription factor binding sites within these enhancer regions has been an important step toward understanding how SCL is regulated: the −4 enhancer contains two E twenty-six (ETS) sites [16]; the +19 enhancer contains an ETS/ETS/GATA motif [17]; and the +40 enhancer contains two GATA/E-Box motifs [15]. Identifying these core transcription factor binding sites within tissue-specific enhancers of SCL has enabled the first attempts to reverse engineer the transcriptional network of HSCs using a bottom-up approach. For example, SCL, FLI1, and GATA2 bind the SCL +19, FLI1 + 12, and GATA2-3 enhancers in primary cells, thus forming a network where all three factors regulate each other to sustain their expression in the absence of other inputs [18]. Other functional outcomes of identifying an enhancer that targets precursor cells capable of generating HSC, progenitors, and endothelial cells include: directing oncogenic fusion genes into stem cells to study their effect on stem cell self-renewal; identifying new cell surface markers for long-term (LT) repopulating HSCs based on their transcriptional identity; and establishing links between tissue ontogeny.

THE FORGOTTEN CHILD: LYL1 IN HEMATOPOIETIC DEVELOPMENT

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. AN ONLY CHILD: SCL IN HEMATOPOIETIC DEVELOPMENT
  5. THE FORGOTTEN CHILD: LYL1 IN HEMATOPOIETIC DEVELOPMENT
  6. BLOOD BROTHERS: SCL AND LYL1 IN ADULT HSCS
  7. SIBLING RIVALRY: SCL AND LYL1 IN ERYTHROID AND MEGAKARYOCYTIC LINEAGES
  8. THE STOLEN CHILDREN: SCL AND LYL1 IN T-ALL
  9. THE FUTURE GENERATION
  10. DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
  11. REFERENCES

Until recently, LYL1 has been the forgotten child. The LYL1 gene encodes a bHLH protein closely related to SCL with 82% amino acid identity in the critical bHLH domains including the conserved residues important for interaction to LMO2. Unlike SCL, LYL1 is dispensable for hematopoietic development, although normal survival of LYL1LacZ knockin embryos requires both copies of SCL [19, 20]. LYL1LacZ knockin mice express a LacZ chimeric protein retaining the N terminus and DNA-binding basic region of LYL1. This targeting strategy has allowed mapping of LYL1 expression in development but raises the possibility that the retained N terminus might have residual function. However, generation of a LYL1 KO allele has recently confirmed redundancy of LYL1 in development [21].

The inability of LYL1 to compensate for SCL in hematopoietic development may be explained by the lack of LYL1 expression at the critical stage of FLK1+ hemangioblasts. Analysis of LYL1LacZ mice revealed a lack of β-galactosidase activity in the Yolk-Sac (YS) and early AGM (7.5-8.0) despite detectable mRNA [22]. This contrasts with SCLLacZ knockin mice where β-galactosidase activity in the YS and AGM matches mRNA expression. The discrepancy between β-galactosidase protein and LYL1 mRNA may be explained by retention of the N terminus of LYL1 in LYL1LacZ mice, which contains a PEST-rich motif that promotes proteosomal degradation of LYL1 [23]. To address the possibility that LYL1 is not expressed during the appropriate developmental period, we have recently generated SCLLYL1 knockin mice in which a LYL1 cDNA cassette is expressed under the control of SCL regulatory elements (J.M.S., unpublished data). Homozygous SCLLYL1 mice have a bloodless phenotype identical to homozygous SCLLacZ mice, suggesting that differences in the expression of SCL and LYL1 are not the explanation for the inability of LYL1 to compensate for SCL in hematopoietic development.

Comparative genomic sequence analysis of human, mouse, and dunnart LYL1 loci was used to characterize the LYL1 promoter [24] (Fig. 2B). The LYL1 promoter has two GATA binding sites and two ETS binding sites, reminiscent of the arrangement in the promoter and enhancers of its paralog, SCL. However, unlike the SCL promoters, a highly conserved 464 bp region of the LYL1 promoter is sufficient to target reporter expression to embryonic blood and endothelium, including blood clusters in the AGM similar to the staining pattern observed in the LYL1LacZ embryos [20]. In vivo foot printing analysis combined with chromatin immunoprecipitation and stable transfection assays in blood and endothelial cell lines have shown that LYL1 and SCL share common upstream transcriptional regulators that include the ETS factors (FLI1, ELF1, and ERG) and GATA2 [20, 24]. Taken together with data from rescue experiments in SCL KO ESCs (see below), the functional differences between these paralogs in hematopoietic development are likely accounted for by differences in the proteins rather than the upstream transcriptional program, which appears to be similar for both.

Based upon a number of observations using SCL KO ESCs, we speculate that the N or C termini of LYL1 inhibit hematopoietic development (Fig. 1A). First, enforced expression of full-length LYL1 is unable to promote hematopoietic development for SCL KO ESCs [20]. Second, the bHLH domains of SCL are sufficient for hematopoietic development [5]. Third, the HLH domain of LYL1 can substitute for that of SCL because LYL1 contains the conserved amino acids required for binding to LMO2 [7, 8]. Finally, although the DNA-binding preference for SCL and LYL1 is slightly different, DNA binding is dispensable for hematopoietic development [5, 6]. It is unclear which terminus of LYL1 is inhibitory, although the N terminus of LYL1 binds the cyclic AMP-responsive element binding protein, CREB1, which can activate expression of an inhibitor of ESC differentiation, ID1 [25].

BLOOD BROTHERS: SCL AND LYL1 IN ADULT HSCS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. AN ONLY CHILD: SCL IN HEMATOPOIETIC DEVELOPMENT
  5. THE FORGOTTEN CHILD: LYL1 IN HEMATOPOIETIC DEVELOPMENT
  6. BLOOD BROTHERS: SCL AND LYL1 IN ADULT HSCS
  7. SIBLING RIVALRY: SCL AND LYL1 IN ERYTHROID AND MEGAKARYOCYTIC LINEAGES
  8. THE STOLEN CHILDREN: SCL AND LYL1 IN T-ALL
  9. THE FUTURE GENERATION
  10. DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
  11. REFERENCES

SCL is expressed in adult HSCs with highest expression in the Kit+ Sca1+ Lin CD150+ CD48 subpopulation, which is enriched for LT-HSCs [26]. LYL1 is also expressed in HSCs, although single-cell expression analysis of HSCs suggested that LYL1 and SCL are expressed in distinct HSC populations [27].

To overcome the embryonic lethality of SCL KO mice, conditional KO mice (SCL cKO) were generated to examine the function of SCL in adult hematopoiesis [28]. Surprisingly, deletion of SCL in the adult HSCs did not lead to stem cell failure as anticipated, although we observed a modest defect in short-term (ST)-HSC activity [29]. An important role for SCL in human and mouse HSC function has been confirmed using shRNA [26, 30]. How SCL regulates ST-HSC function may be due to reduced expression of the cell cycle inhibitor CDKN1a (p21) or ID1 [26]. Both p21 and ID1 are reported target genes of SCL, and reduced expression impairs HSC function, especially in the setting of stress hematopoiesis.

The observation that SCL and LYL1 were expressed in distinct subsets of HSCs led to the hypothesis that SCL cKO hematopoiesis was maintained by LYL1-expressing HSCs. To address this hypothesis, we crossed SCL cKO mice with LYL1LacZ knockin mice [31]. Following deletion of SCL, we observed loss of activity over 2–4 weeks associated with apoptosis [31]. Thus, maintenance of adults HSCs requires either SCL or LYL1 (Fig. 1B). SCL/LYL1 double KO cells could be used to identify key target genes in HSCs, although the rapid loss of these cells will be problematic.

By combining transcription factor gene expression data in HSCs with genome-wide ChIP-seq using the hematopoietic progenitor cell line HPC-7 as a surrogate for HSCs and unbiased motif discovery platforms, a comprehensive catalog of transcription factor interactions has now been mapped with 10 factors (SCL, LYL1, LMO2, GATA2, RUNX1, MEIS1, PU.1, ERG, FLI1, and GFI1b) showing overlapping binding suggestive of combinatorial interactions between these transcription factors in HSCs [4, 32–34] (Fig. 1B). In addition to these regulatory networks, components of this complex bind to and transactivate a large number of known and unknown regulators of HSC function [32]. Although most of the target genes contained an E-box binding motif, consensus binding motifs for RUNX1, ETS, GATA, and MEIS were highly overrepresented, indicating cooperation between SCL and other major hematopoietic regulators. Interestingly, ChIP-seq using a LYL1 antibody demonstrated a very different pattern of transcription factor binding compared with SCL, with the majority of binding peaks over intragenic or intergenic sites rather than within ±1 kb of transcription start sites [33].

SIBLING RIVALRY: SCL AND LYL1 IN ERYTHROID AND MEGAKARYOCYTIC LINEAGES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. AN ONLY CHILD: SCL IN HEMATOPOIETIC DEVELOPMENT
  5. THE FORGOTTEN CHILD: LYL1 IN HEMATOPOIETIC DEVELOPMENT
  6. BLOOD BROTHERS: SCL AND LYL1 IN ADULT HSCS
  7. SIBLING RIVALRY: SCL AND LYL1 IN ERYTHROID AND MEGAKARYOCYTIC LINEAGES
  8. THE STOLEN CHILDREN: SCL AND LYL1 IN T-ALL
  9. THE FUTURE GENERATION
  10. DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
  11. REFERENCES

In mature cell lineages, SCL expression is restricted to the erythroid, megakaryocyte, and mast cells. LYL1 expression is more ubiquitous with expression also in myeloid cells and B cells. A 5 kb element containing the SCL +40 enhancer displays activity in primitive and definitive erythroblasts through two conserved GATA/E-box motifs that bind GATA1 and SCL [15]. Erythroid expression of LYL1 is regulated by conserved GATA motifs in the LYL1 promoter. GATA2 binding activates expression of LYL1, while GATA-1 binding represses LYL1 expression during erythroid maturation [20].

SCL expression is not required for LT maintenance of red cells or platelets, although SCL cKO mice have a moderate anemia and thrombocytopenia [35]. In erythropoiesis, SCL appears to be most important for growth of blast forming units-erythroid (BFU-e) with sparing of colony forming units-erythroid (CFU-e) (Fig. 1C). SCL cKO red cells also have reduced expression of TER119, a protein associated with Glycophorin A, which is a known target gene of SCL. A similar although not identical erythroid phenotype is observed in mice carrying a germline DNA binding mutation of SCL, suggesting that many of the nonredundant functions of SCL in erythropoiesis are mediated by DNA binding [6]. In contrast to SCL, LYL1LacZ KI mice have normal erythroid progenitor growth but features of red-cell hemolysis, suggesting a role for LYL1 in red-cell maturation [36]. It remains to be proven that on-going red-cell and platelet production in the setting of SCL or LYL1 KO mice is due to functional redundancy like that observed in HSCs.

In erythroid cells, SCL forms a multiprotein complex with GATA1, LMO2, and LDB1 to bind E-box/GATA sites in erythroid-specific proteins such as EPB4.2 and EKLF. Assembly of this complex is augmented by single-strand DNA binding proteins (SSBP2 and SSBP3), which inhibit E3 ligase ubiquitination of LDB1 [37]. During early erythropoiesis, SCL is associated with corepressors including histone deacetylases, mSIN3a, BRG1, LSD1, ETO-2, GFI1b, and the core-binding factor subunit CBFA2T3H [38, 39]. The composition of the SCL complex changes with erythroid maturation, acquiring transcriptional coactivators such as p300 and P/CAF [40] (Fig. 1C). The SCL complex also mediates long-range chromatin looping between the locus control region (LCR) enhancer and the globin promoters, necessary for the developmental switch from γ-globin to β-globin and migration of the β-globin locus to transcription factories rich in hyperphosphorylated RNA polymerase II [41].

CASTing experiments in erythroid cell lines identified a bipartite binding motif comprising an E-box and GATA motif separated by 9 bp. While this classic bipartite motif is relatively rare, recent ChIP-seq analyses for SCL and GATA1 have identified a more common composite motif comprising a half E-box and GATA separated by 7–9 bp [42]. This identified not only known target genes (SCL itself, EKLF, α-globin, β-globin, EPB4.2, and Glycophorin A) but also many potential novel targets regulating a wide range of biological processes [42]. The majority of these targets require direct DNA binding by SCL, as demonstrated by ChIP-seq analyses of fetal liver cells from DNA binding mutant mice [42]. Surprisingly, loss of SCL binding altered gene expression in only 4% of genes despite marked changes in binding peaks. This may reflect functional redundancy by LYL1, which has an almost identical binding preference to SCL.

Studies using SCL cKO mice have shown that SCL is important for megakaryocyte progenitor growth and platelet shedding, particularly in response to stress [43]. Detailed studies of megakaryopoiesis in LYL1LacZ mice have yet to be reported, although these mice have normal platelet numbers [36]. Potential target genes of SCL in megakaryocytes include NFE2, MEF2C, and p21 [43–45]. In the case of p21, SCL functions as a repressor of p21 by recruitment of ETO-2 during megakaryocyte proliferation and polyploidization [44]. MEF2C is also required for B-cell development, which may explain the B-cell defects observed in LYL1LacZ mice [19]. Genome-wide binding studies in primary megakaryocytes demonstrated the presence of an activating five factor complex (SCL, GATA1, GATA2, RUNX1, and FLI1) similar to that found in progenitor cells but with minimal overlap of binding peaks, indicating a lineage-specific role for multifactor combinatorial binding [46] (Fig. 1C).

SCL and LYL1 may also play a role in lineage commitment. Loss of SCL in megakaryocyte erythroid progenitors leads to aberrant mast cell differentiation, perhaps due to increased expression of GATA2 [47]. The observation of increased CD61+ cells in SCL DNA binding mutant mice suggests that SCL may promote erythropoiesis at the expense of megakaryocyte formation [6].

THE STOLEN CHILDREN: SCL AND LYL1 IN T-ALL

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. AN ONLY CHILD: SCL IN HEMATOPOIETIC DEVELOPMENT
  5. THE FORGOTTEN CHILD: LYL1 IN HEMATOPOIETIC DEVELOPMENT
  6. BLOOD BROTHERS: SCL AND LYL1 IN ADULT HSCS
  7. SIBLING RIVALRY: SCL AND LYL1 IN ERYTHROID AND MEGAKARYOCYTIC LINEAGES
  8. THE STOLEN CHILDREN: SCL AND LYL1 IN T-ALL
  9. THE FUTURE GENERATION
  10. DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
  11. REFERENCES

Expression of SCL and LYL1 is limited to early T-cell development, although the pattern of expression differs between mouse and human [48]. Murine SCL transcription is detectable up to the double negative (DN)3 stage, while in humans, SCL mRNA is not detectable. In contrast, murine LYL1 transcription is restricted to the DN1 stage, while in humans, LYL1 mRNA is detectable up to the immature single positive stage. Absence of either factor has no detrimental effect on T-cell development [19]. In this case, this is unlikely to be due to functional redundancy because LMO2 is also not required for T-cell development.

Aberrant expression of either SCL or LYL1 is frequently observed in T-ALL due to chromosomal translocation, microdeletions, or more commonly transactivating mechanisms such as abnormal expression of other factors within the regulatory network such as LMO2 [49, 50]. Aberrant expression of SCL or LYL1 leads to T-ALL in animal models, although additional mutations such as activation of Notch1 are required. Recent studies of the preleukemic phenotype of these animal models suggest that both SCL and LYL1 cause T-ALL by inducing aberrant self-renewal of committed T cells in the thymus, which provides a cellular pool for acquiring additional mutations [49, 51] (Fig. 1D).

The DNA binding domain of SCL is not required for T-cell oncogenesis, suggesting that SCL functions either through inhibition of E homodimer function or SCL represses or activates target genes through other DNA binding proteins such as GATA3 [52]. ChIP-seq comparisons of SCL binding in erythroid and T-ALL cells revealed very little overlap with enrichment for RUNX, ETS1, and an E-box variant CAGGTG binding sites in T-ALL cells [53] (Fig. 1D).

THE FUTURE GENERATION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. AN ONLY CHILD: SCL IN HEMATOPOIETIC DEVELOPMENT
  5. THE FORGOTTEN CHILD: LYL1 IN HEMATOPOIETIC DEVELOPMENT
  6. BLOOD BROTHERS: SCL AND LYL1 IN ADULT HSCS
  7. SIBLING RIVALRY: SCL AND LYL1 IN ERYTHROID AND MEGAKARYOCYTIC LINEAGES
  8. THE STOLEN CHILDREN: SCL AND LYL1 IN T-ALL
  9. THE FUTURE GENERATION
  10. DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
  11. REFERENCES

Much has been learnt since the discovery of SCL and LYL1 more than 20 years ago. In particular, the development of new mouse models and the use of genome-wide binding studies have been significant progress. More detailed studies of their disparate N and C termini are required to understand how these two family members have both shared and distinct functions in hematopoiesis. Hopefully, this will soon bring us full circle back to their origins, where this knowledge can be used for molecular targeting of the bHLH complex in T-ALL.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. AN ONLY CHILD: SCL IN HEMATOPOIETIC DEVELOPMENT
  5. THE FORGOTTEN CHILD: LYL1 IN HEMATOPOIETIC DEVELOPMENT
  6. BLOOD BROTHERS: SCL AND LYL1 IN ADULT HSCS
  7. SIBLING RIVALRY: SCL AND LYL1 IN ERYTHROID AND MEGAKARYOCYTIC LINEAGES
  8. THE STOLEN CHILDREN: SCL AND LYL1 IN T-ALL
  9. THE FUTURE GENERATION
  10. DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
  11. REFERENCES