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Current Opinion in Hematology:
doi: 10.1097/MOH.0000000000000052
HEMATOPOIESIS: Edited by Hal E. Broxmeyer

Kit and Scl regulation of hematopoietic stem cells

Rojas-Sutterlin, Shantia,b; Lecuyer, Ericc,d; Hoang, Tranga,b,d,e

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Author Information

aInstitute of Research in Immunology and Cancer, University of Montreal

bMolecular Biology Program, Faculty of Medicine, University of Montreal

cInstitut de Recherches Cliniques de Montreal (IRCM)

dDepartment of Biochemistry

eDepartment of Pharmacology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada

Correspondence to Trang Hoang, PhD, Institute for Research in Immunology and Cancer (IRIC), University of Montréal, P.O. Box 6128, Downtown Station, Montréal, QC, Canada H3C 2J7. Tel: +1 514 343 6970; e-mail:

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Purpose of review

KIT tyrosine kinase receptor is essential for several tissue stem cells, especially for hematopoietic stem cells (HSCs). Moderately decreased KIT signaling is well known to cause anemia and defective HSC self-renewal, whereas gain-of-function mutations are infrequently found in leukemias. Thus, maintaining KIT signal strength is critically important for homeostasis. KIT signaling in HSCs involves effectors such as SHP2 and PTPN11. This review summarizes the recent developments on the novel mechanisms regulating or reinforcing KIT signal strength in HSCs and its perturbation in polycythemia vera.

Recent findings

Stem cell leukemia (SCL) is a transcription factor that is essential for HSC development. Genetic experiments indicate that Kit, protein tyrosine phosphatase, nonreceptor type 11 (Ptpn11), or Scl control long-term HSC self-renewal, survival, and quiescence in adults. Kit is now shown to be centrally involved in two feedforward loops in HSCs, one with Ptpn11 and the other with Scl.


Knowledge of the regulatory mechanisms that favor self-renewal divisions or a lineage determination process is central to the design of strategies to expand HSCs for the purpose of cell therapy. In addition, transcriptome and phosphoproteome analyses of erythroblasts in polycythemia vera identified lower SCL expression and hypophosphorylated KIT, suggesting that the KIT–SCL loop is relevant to the pathophysiology of human blood disorders as well.

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How hematopoietic stem cells (HSCs) self-renew to support the lifelong production of blood cells has been intensively studied, providing unique insights into the importance both of cellular interactions during development and homeostasis, and of cellular programming by transcription factors that shape cell identity and functions. This understanding has important implications in stem-cell-based therapy and HSCs serve as paradigm for the stem cell field in general.

HSCs reside in specialized niches and KIT is essential for HSC interaction with the niche, controlling HSC self-renewal, survival, and quiescence. Two recent publications implicate KIT in two feedforward loops in HSCs, one with the stem cell leukemia/T-cell acute leukemia 1 (SCL/TAL1) transcription factor and the other with protein tyrosine phosphatase, nonreceptor type 11 (PTPN11) [1,2▪▪]. Feedforward loops during development serve to consolidate tissue identity. In addition, feedforward loops may tip a metastable system toward a lineage. Indeed, HSCs are heterogeneous with respect to their developmental potential in time (long term versus intermediate and short term) [3▪▪] and more recently with respect to biased lineage potentials [4▪].

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Mutations at the W locus in mice were first described almost a century ago [5]. These mutations were later linked to anemia and defective numbers of spleen colony-forming units, which were the first quantitative and closest assays for HSCs in the 1960s [6]. It took more than 20 years of insight from numerous biological studies and convergence with the field of viral oncogenes to map the Kit gene, encoding a tyrosine kinase receptor [7], to the W locus in mice [8]. It then became clear that the gene encoding Kit ligand (Kitlg) should map to the Sl-locus [9–11]. Signals mediated by Kit ligand (KITLG) act preferentially on primitive multipotent hematopoietic progenitors, favoring their self-renewal as assessed by colony replating assays [12]. Remarkably, the Sld mutation causing the production of soluble but not transmembrane KITLG [13] mirrors W defects in vivo, indicating the critical importance of direct cell–cell contact between HSCs and the stem cell niche.  

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Despite this genetic evidence of the importance of cell–cell interaction on HSC biology, the identification of signal sending cells in the niche has been hindered by the diversity of cell types and the relatively limited access to distinctive lineage markers within the niche. Reconstructing an environment that mimics the niche signals suitable for HSC expansion is a challenge in regenerative medicine. KITLG, also referred to as stem cell factor, mast cell growth factor, or steel factor, is produced by the endothelial cells, mesenchymal cells, and osteoblasts. A recent study unravels the importance of arteriolar niches in sustaining HSC quiescence and long-term self-renewal [14▪▪]. Using a cell-type-specific green fluorescent protein (Gfp) knockin strategy, Ding et al.[15▪▪] demonstrated the importance of perivascular stromal cells and endothelial cells as producers of KITLG in adult mice. Deletion of Kitlg in either cell type is detrimental to HSCs in vivo. Obviously, KITLG does not stand alone. An understanding of the contribution of other niche components, such as chemokines [16], cytokines, and adhesion molecules (reviewed by [17]), will undoubtedly bring us closer to niche reconstruction.

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Early studies point to the essential role of KIT in hematopoiesis. Therefore, KIT or Cluster of differentiation 117 (CD117) has been widely used as a marker of stemness in the hematopoietic system, along with co-expression of stem cell antigen-1 (SCA-1) and lack of lineage markers (Fig. 1). As hematopoietic progenitors lacking stem cell activity are also KIT+ and respond to ligand stimulation, the intriguing question then becomes how the same ligand can have different biological outcomes in different cell types, controlling self-renewal division in HSCs and cell division in erythroid progenitors that are programmed to differentiate. At the functional level, detailed characterization of the hematopoietic defects in a series of W mutant mice with varying KIT signaling strengths suggest that long-term reconstituting HSCs (LTR-HSCs) are less tolerant to subtle variations in KIT signaling compared with myeloid progenitors, as exemplified by the stem cell defects in W41/41 mutant mice monitored in transplantation assays, whereas colony-forming cells appeared normal [18].

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Fetal HSCs divide rapidly to expand the stem cell pool and abruptly switch to a more slowly dividing ‘quiescent’ state at 4 weeks after birth [19], with an estimated doubling time of 36–145 days [20]. Remarkably, Kit has been shown to control HSC quiescence [21]. The decreased capacity of HSCs from W41/41 mice for long-term reconstitution, which was rigorously defined in primary and secondary transplantation assays, has been associated with a decreased proportion of cells in G0 as assessed by standard 4′,6-diamidino-2-phenylindole (Dapi)-Ki67 staining and also by low bromodeoxyuridine (BrdU) labeling. These results highlight the importance of Kit for HSC quiescence and long-term maintenance. How does Kit control HSC quiescence? The transmembrane protein cluster of differentiation 81 (CD81), a member of the tetra spanning family, has been shown to facilitate the return to quiescence of HSCs after acute exposure to a proliferative stress and to sustain HSC self-renewal [22▪]. Interestingly, CD81 co-immunoprecipitates with KIT and co-localizes with KIT in a megakaryoblastic cell line, MO7-E [23–25] (Fig. 2). As both KIT and CD81 are highly expressed in LTR-HSCs (, it is tempting to speculate that this interaction also occurs in HSCs and controls the HSC quiescence state. Two other proteins interacting with KIT, PTPN11 and Casitas B-lineage lymphoma (CBL) (Fig. 2), have also been shown to control HSC quiescence (reviewed in [26]).

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One challenge in stem cell studies is the need to demonstrate that purified cell populations have the expected reconstitution potential in transplantation assays. Several studies concur to show that HSCs purified in S-G2M fail to engraft [19,27], but when these cells are allowed to return to G0 under the influence of transforming growth factor beta, for example, engraftment was observed. With the provision that the study was done at the population level and not at the single-cell level [19], these results raise the question of whether HSCs are truly dormant or not. Adding to this is the problem that BrdU administration, which is commonly used to determine the HSC proliferative status, actually triggers HSCs into cell cycle [20]. No less confounding is the fact that polyinosinic-polycytidylic acid treatment to induce Mx1 promoter inducible Cre recombinase (MxCre)-dependent gene excision of floxed alleles induces an interferon response that also sends HSC into cycle. Therefore, the common tool kit which is otherwise so powerful in molecular genetics and cell biology requires cautious adjustments when applied to such a rare and heterogeneous population of HSCs. Nonetheless, most in-situ gene inactivation so far that affects HSC quiescence also has an impact on long-term self-renewal activity, providing strong genetic evidence in favor of a functional link between these two HSC properties (reviewed in [26]).

In this context, two recent studies clarified KIT expression levels in HSCs. Within a highly purified population of HSCs, CD150+CD48LinSCA+KIT+, these authors show that KIT expression levels can vary by as much as 20-fold. Without questioning the fact that HSCs are KIT+, the study shows that low KIT expression in this purified population corresponds to cells with a quiescence status [28]. Interestingly, Shin et al.[29▪] provide detailed functional evidence that HSCs with high KIT levels demonstrate impaired self-renewal activity compared with HSCs with lower KIT levels. When analyzed at the single-cell level, these KIThi cells exhibit an intrinsic megakaryocyte bias, producing more megakaryocytes in culture compared to KITlo cells. These authors also show that high KIT levels correspond to high KIT signaling, as assessed by the levels of phospho-signal transducer and activator of transcription 3 (STAT3) and phospho-signal transducer and activator of transcription 5 (STAT5), as well as functional requirement for higher KIT signaling levels, using timed imatinib treatment to differentially affect the KIT activity in KIThi versus KITlo cells. Therefore, higher KIT signaling favors the megakaryocyte fate in multipotent progenitors, in line with the observations that megakaryocyte–erythroid progenitors (MEPs) also express higher Kit messenger RNA (mRNA) levels, compared with other lineage affiliated progenitors.

KIT has been shown to entertain functional interactions with other cell-surface receptors, including erythropoietin receptor (EPOR) in erythroid progenitors [30], interleukin-7 receptor alpha (IL7RA) in lymphoid progenitors [31], and platelet-derived growth factor alpha (PDGFRA) in gastrointestinal tumors, in which KIT expression marks a population with stem cell properties [32]. As lineage-restricted receptors are not expressed at detectable levels in HSCs, these differing protein–protein interactions that are dictated by the cellular context could determine the outcome of KIT signaling in these cells.

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Despite this extensive characterization of KIT function and signal transduction pathways, only few studies have investigated the regulation of Kit gene expression. A possible role for specificity protein 1 (SP1) [33], MYB, and ETS2 [34] in activating the proximal promoter was reported. These transcription factors per se are not sufficient to explain the tissue-specific expression of Kit and, in particular, in HSCs. Krosl et al.[35] showed that KITLG favors the survival of the human CD34+ hematopoietic cell line TF1. In this context, downregulation of SCL basic helix–loop–helix (bHLH) transcription factor impaired the survival of TF1 cells, because of a downregulation of KIT mRNA and protein levels. Although these studies indicated a functional correlation between Kit and Scl, it was not known whether Kit acts upstream or downstream of Scl.

A direct demonstration that Kit is a target gene of SCL was provided by Lecuyer et al.[36] using a combination of transient luciferase reporter assays in a heterologous cell model and chromatin immunoprecipitation (ChIP) studies in TF1 cells. Surprisingly, the Kit proximal promoter lacks canonical binding sites for the SCL complex. This study revealed that SCL forms part of a multifactorial complex, also containing the E2A, GATA-2, LMO2, and LDB1 proteins, which are recruited to the Kit promoter via physical interactions with promoter-bound SP1, leading to transcriptional activation. Accordingly, the DNA-binding domain of SCL is dispensable for Kit promoter activation. The recent crystal structure of (SCL:E47)bHLH:LMO2:LDB1LID bound to DNA revealed the molecular details of LMO2 interaction with SCL that, as a consequence, strengthened SCL:E2A heterodimerization while weakening SCL:E2A DNA binding, therefore explaining these DNA-binding independent activities [37▪]. These multimeric complexes exhibit multifunctionality in transcription regulation [38]. Concurring with these early studies, recent genome-wide identification of SCL target genes by ChIP-seq identified SCL peaks in the regulatory region of the Kit gene [39,40].

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SCL is required for the generation of all hematopoietic lineages during ontogeny as SCL specifies mesoderm to a hematopoietic and vascular fate ([41,42], for a recent review [26]). Scl-deficient embryos die at E9.5 because of the lack of primitive erythroid cells. In contrast, the role of SCL in adult HSCs is controversial as Scl appears to be dispensable in conditional knockout mouse models [43,44], but essential in mouse chimeras [45] and in human cells [46,47]. The existence of various isoforms of SCL with differing properties further complicates the issue [48–50]. Nonetheless, all studies concur to demonstrate an important role for SCL in the erythroid and megakaryocyte lineages, in which Scl expression is highest [43,51–53] and erythroid target genes are well documented [39,54–56]. Moreover, dynamic variations in the composition of SCL-containing complexes have been shown to control the transition between a proliferative state and commitment to terminal differentiation [57]. Perhaps, a more fundamental question is whether or not multipotentiality, the cell cycle status of HSCs, and their long-term activities are co-ordinately regulated by a converging network of molecular players.

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Scl expression is highest in the KSL 150+48 population [45], suggesting that Scl is important for HSC functions. SCL controls hematopoietic cell survival at different developmental stages. During embryonic development, Scl acts in the same genetic pathway as Vegf-Flk1 to sustain the survival of erythroid cells in the yolk sac [10,58,59]. An antiapoptotic role for Scl was also reported in several cell types [60–62], in particular in human CD34+ cells maintained with KITLG [63]. In murine HSCs, Scl controls cell survival and this activity is redundant with lymphoblastic leukemia 1 (Lyl1) [64].

Scl involvement in the regulation of HSC quiescence has been recently addressed. Venezia et al.[65] first reported the quiescence signature in HSCs and Scl was found to be part of this signature. Accordingly, within the population of purified KSL 150+48, Lacombe et al.[45] found that Scl transcripts are higher in quiescent HSCs (G0 phase) compared with more active HSCs (G1/S/G2M phase). Significantly, the G0–G1 transition was abnormal in HSCs- in which Scl gene dosage was decreased (Scl+/-) or Scl levels disrupted by RNA interference. Together, these results indicate that SCL controls HSC quiescence. Moreover, this altered cell cycle transit was specific to the fraction of KSL 150+48 HSCs and was not observed in the less purified fraction Sca+Kit+Lin[45], in which only 1 in 10 cells have long-term in-vivo reconstitution potential. Therefore, some of the controversies around HSC quiescence status may be attributed to the various gating strategies used in flow cytometry analysis.

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Whether Scl is required for stem cell function has been a matter of debate, as several functional studies have come to different conclusions.

Scl+/– HSCs showed impaired competitive potential 4 months after transplantation when transplanted at limiting numbers (4 colony repopulating units equivalent). In contrast, when cells were transplanted at saturating doses (40 colony repopulating units), impaired reconstitution was not observed at 4 months but at a later timepoint (8 months after transplantation) [45]. These observations indicate that long-term stem cell functions are underestimated at the commonly used 4 months window and require appraisal at 6–8 months following transplantation [45]. This was supported by an independent study indicating that a 4-month readout essentially monitors a wave of HSCs with intermediate but not long-term potential [3▪▪]. Furthermore, Scl+/– HSCs exhibit impaired repopulation capacity after secondary transplantation [45]. In agreement with this, SCL RNA interference in human cord blood CD34+ cells drastically impairs their reconstitution potential in xenografted immune-deficient mice [46]. Conversely, Reynaud et al.[47] showed that enforced Scl expression increases the long-term stem cell regenerative potential in secondary transplantation. Finally, Hall et al.[52] also reported that Scl deletion impaired multipotent progenitors [colony-forming unit – spleen (day 12)] which formed smaller colonies. In contrast, using MxCre conditional deletion (SclΔ/Δ), Mikkola et al.[43] showed that Scl is dispensable in HSCs when transplanted mice were monitored after 6 months. In secondary transplantation, SclΔ/Δ cells were able to reconstitute the bone marrow, spleen, and thymus, and to maintain the KSL pool as efficiently as control cells (Scl+/Δ). Similarly, Curtis et al.[44] indicated that Scl deletion (SclΔ/Δ) caused a bilineage defect 4 weeks after transplantation and multilineage defect after 16 weeks. Despite this, SclΔ/Δcells persisted in secondary transplantation.

These apparent discrepancies may be explained by different factors. The most obvious is the redundancy factor, be it with homologous genes, neighboring genes, or within an intricate gene network that allows hematopoiesis to remain relatively stable in the face of intrinsic or extrinsic perturbations. For example, Kit, fetal liver kinase 1 (Flk1), and Pdgfra are neighboring genes on mouse chromosome 5 [66] and Kit is redundant (possibly with Flk1) during embryonic development but not in the adult. The SCL transcription factor is highly homologous to LYL1 in the bHLH domain (Fig. 3) and both genes are involved in chromosomal translocations in T-cell acute lymphoblastic leukemia, suggesting that these genes may have overlapping activities. Souroullas et al.[64] provided genetic evidence for a functional redundancy between Scl and Lyl1 in adult HSCs by showing that Scl is haploinsufficient in the absence of Lyl1. Therefore, both Scl alleles are required to compensate for the absence of Lyl1 in HSCs and, conversely, Lyl1 can compensate for decreased Scl gene dosage in HSCs. Such redundancy was also reported for GATA binding protein-1 (Gata1) and GATA binding protein-1 (Gata2) during development [67]. It was suggested that redundancy might in fact be evoked by the gene knockout itself. To address the question of Scl-Lyl1 redundancy, Chan et al.[68] studied the onset of primitive erythropoiesis in embryonic stem cells in culture. Scl–/– embryonic stem cells are unable to undergo hematopoietic differentiation. This defect can be rescued by ectopic Scl but not Lyl1 expression, indicating that Lyl1 cannot fulfill all Scl functions [68]. In line with these observations, Wilson et al.[40] showed by ChIP-seq analysis of a multipotent cell line that SCL peaks are equally distributed between promoter, intragenic, and intergenic regions, whereas LYL1 peaks are almost exclusively found in intragenic and intergenic regions. Therefore, SCL and LYL1 do not normally occupy the same regions of the genome. Perhaps, LYL1 can occupy these promoters only when Scl is deleted and thus redundancy may not occur during homeostasis, but rather is induced by Scl deletion. Strikingly, an interrogation of the data published by Wilson et al.[40] indicate that SCL occupies both Kit and Cd81 loci in multipotent cells, consistent with the view that both are part of a quiescence gene-expression program controlled by SCL in HSCs. This remains to be addressed using the genetic strategy described by Souroullas et al.[64].

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In primary bone marrow cells, Kit was found to be co-expressed with Scl[36], using the ScllacZ mice to track Scl gene expression [69]. Moreover, conditional Scl deletion in a Lyl1–/– background decreases the numbers of KIT+Lin and KIT+SCA+Lin cells [64]. These observations fit well with the view that SCL is upstream of KIT and activates Kit transcription, but do not exclude the possibility that SCL can also function downstream of KIT.

Recent evidence suggests that the clonal expansion of KIT+ multipotent and erythroid progenitors and their sensitivities to KITLG stimulation are determined by the SCL levels [1]. In addition, increasing SCL levels in hematopoietic cells is sufficient to correct the hematopoietic deficiencies in W41/41 mice. Significantly, W41/41 mice showed decreased common myeloid progenitors, decreased MEPs, and modestly but significantly decreased hematocrits and increased mean corpuscular volume, indicative of anemia [1,70]. All of these parameters were rescued by transgenic SCL expression. Mutations in the Kit gene that impair Kit function in these mice clearly rule out the possibility that the genetic rescue might be because of increased Kit levels. Rather, these results indicate that Scl operates downstream of Kit. As Scl is also upstream of Kit, the results support the view that Scl and Kit establish a feedforward loop in multipotent and megakaryocyte–erythroid progenitors. Such a feedforward loop may explain the observations that KIThi HSCs have a megakaryocyte bias [29▪].

Strikingly, another feedforward loop was reported, involving Src homology 2 (SH2) domain containing protein tyrosine phosphatases (SHP2)–KIT–SHP2 controlling HSC quiescence and self-renewal activity [2▪▪]. SHP2, also referred to as PTPN11, directly interacts with KIT [71] and functions downstream of KIT. Moreover, PTPN11 controls Kit expression via Gata2 but not Scl nor Sp1[2▪▪]. Finally, Ptpn11 deficiency mimics Kit deficiency in HSCs, with decreased quiescence, increased proliferation, and exhaustion [72,73]. Therefore, Ptpn11 controls HSC quiescence and self-renewal in the same way as KIT.

In addition to PTPN11, KIT signaling in HSCs activates multiple pathways that include JAK2-STAT3/5, LNK, phopsholipase C gamma (PLCγ), and extracellular signal regulated kinase (ERK; for a recent review [74]). The pathway downstream of KIT that leads to SCL remains to be investigated. The data reported by Zhu et al.[2▪▪] suggest that it is parallel to PTPN11. A recent study on the transcriptome and phosphoproteome of polycythemia vera associated with the gain-of-function JAK2V617F mutation showed several intriguing molecular features [75▪]. STAT2/STAT3/STAT5 were phosphorylated as expected and ERK activation appeared normal. Surprisingly, KITY719 was hypophosphorylated, and this was associated with decreased SCL mRNA levels. These observations suggest that SCL mRNA levels in KIT+ cells could be controlled by KITY719, via pathways that are parallel to ERK, JAK-STAT, or PTPN11. These questions can be addressed with the tool ‘kit’ that has so much expanded since the discovery of W mutant mice.

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In summary, we propose that a double feedforward loop shapes cell fate in HSCs, multipotent progenitors, and MEPs (Fig. 4) involving at the top Scl-Kit and on the other side Ptpn11-Kit, such that a tip toward high KIT signaling favors the megakaryocytic lineage, whereas a balance toward low KIT signaling favors self-renewal divisions and sustains LTR-HSC functions.

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The infrastructure of IRIC is supported in part by a group grant from the Fonds de Recherche du Québec en Santé (FRQS). This work was funded by the grants from the Canadian Institutes for Health Research (CIHR), the Canadian Cancer Society Research Institute (CCSRI – to T.H. and E.L.), the Leukemia Lymphoma Society of Canada, the Cancer Research Society Inc. and the MERST Québec (to T.H.), and by studentships from FRQS (to S.R.-S.) and the Jean-Guy Mongeau Foundation (to S.R.-S.). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of this article.

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Conflicts of interest

The authors declare no competing financial interest.

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Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest

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Using a conditional Shp2 knockout mouse, the authors show that Shp2 controls stem and progenitor functions. The authors provide genetic evidence for a feedforward loop involving Kit and Shp2 that controls stem cell functions.

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An interesting molecular view of the crystal structure of SCL:E47bHLH:LMO2:LDB-LID bound to DNA illustrating how LMO2:SCL interaction weakens the SCL:E2A association with DNA.

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Decreased SCL mRNA levels and decreased KITY719 phosphorylation in polycythemia vera revealed by global profiling of the transcriptome and phosphoproteome.


feedforward loop; hematopoietic stem cells; KIT; SCL/TAL1; self-renewal

© 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins


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