<i>SCL</i>
            Expression at Critical Points in Human Hematopoietic Lineage Commitment

Zhang, Yanjia; Payne, Kimberly J.; Zhu, Yuhua; Price, Mitchell R.; Parrish, Yasmin Khan; Zielińska, Ewa; Barsky, Lora; Crooks, Gay M.

doi:10.1634/stemcells.2004-0260

Cited by 32 publications

(29 citation statements)

References 32 publications

(66 reference statements)

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“…RT-PCR studies with human bone marrow progenitors support this conclusion in that SCL/TAL1 levels appear to be greater in ST-HSC subsets relative to LT-HSCs. 56 Our studies indicate that Id1 plays a role distinct from SCL/ TAL1 in adult hematopoiesis. Id1-expressing cells are associated with LT-HSC phenotypes, but are reduced in ST-HSC populations For personal use only.…”

Section: Discussionmentioning

confidence: 66%

Id1, but not Id3, directs long-term repopulating hematopoietic stem-cell maintenance

Perry

Zhao

Nie

et al. 2007

Blood

100

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Studies in mice have shown that both LT-and ST-HSCs lack an array of lineage markers (Lin Ϫ ) while simultaneously expressing stem-cell antigen-1 (Ly6A/E; Sca1) and high levels of the receptor tyrosine kinase, c-kit (CD117). 9,10 This phenotype has been abbreviated Lin Ϫ Sca1 ϩ c-kit Hi , or LSK. It constitutes only about 0.5% of whole bone marrow (WBM), but includes a heterogeneous population of HSCs and oligopotent progenitors. In mice expressing the Thy1.1 allele of CD90, HSCs are confined to the LSK subset expressing low levels of this marker (LSK-Thy1.1 Lo ). 11 This represents 0.15% of WBM, and 1 in 22 LSK-Thy1.1 Lo cells transplanted into radiation-conditioned hosts can concurrently repopulate B-cell, T-cell, and myeloid lineages. 12 However, ST multilineage repopulating cells within the LSK-Thy1.1 Lo compartment outnumber LT repopulating cells by 10 to 1, illustrating the paucity of LT-HSCs. Surface markers such as CD27, CD48, CD150, and Flt3/Flk2 (CD135) have been used in independent studies to further define and enrich LT-HSCs, as will be discussed in our results.The ability to identify distinct yet primitive hematopoietic progenitors has made it possible to question the molecular mechanisms governing differentiation between these compartments. The factors governing LT-to ST-HSC differentiation and how these differ from stimuli directing LT-HSC renewal are of special interest due to their potential therapeutic promises. However, characterizing molecular events in HSCs is not trivial due to the scarcity of these bone marrow progenitors and the labor-intensive protocols required to isolate them at high purities. Nevertheless, studies using genetic approaches are beginning to implicate several gene families as influential regulators of these processes. [13][14][15][16][17][18] Among these are the cell-cycle regulators p21 cip1/waf1 and p16 INK4a , which have been shown to influence LT-HSC maintenance by governing depletion of this compartment. [19][20][21] Helix-loop-helix (HLH) transcriptional regulators have also been shown to play a role in HSC maintenance. [22][23][24] These proteins can function as either transcriptional activators or repressors. E-proteins, encoded by E2A, HEB, and E2-2 genes, are a family of activators that may influence HSC maintenance by influencing transcription of p21 cip1/waf1 and p16 INK4a genes. [25][26][27][28] E-proteins are almost ubiquitously present; hence, their transcriptional activity is controlled by expression of one or more inhibitory proteins. One prominent class of E-protein inhibitors is the Id family, which includes Id1 through Id4. Id proteins have HLH domains similar to E-proteins, which allows avid binding to E-proteins to form inactive heterodimers. 29,30 Through this mechanism, Id proteins regulate a wide range of differentiation programs. For example, ectopic expression of Id1 from lymphoidspecific promoters abolishes B-or T-cell development, 31,32 and For personal use only. on May 10, 2018. by guest www.bloodjournal.org From overexpression in bone marr...

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Section: Discussionmentioning

confidence: 66%

Id1, but not Id3, directs long-term repopulating hematopoietic stem-cell maintenance

Perry

Zhao

Nie

et al. 2007

Blood

100

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“…12,16 Interestingly, low TAL1 expression did not affect B-lymphoid production in 5-week LTC, consistent with the absence of TAL1 expression in the B-cell lineage. 30 This also argues against nonspecific effects of shRNA-TAL1 in human progenitors. Altogether, these observations indicate that TAL1 is required in myeloid-restricted progenitors.…”

mentioning

confidence: 99%

Low SCL/TAL1 expression reveals its major role in adult hematopoietic myeloid progenitors and stem cells

Grange

Armstrong

Duval

et al. 2006

Blood

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Stem cell leukemia/T cell acute leukemia 1 (SCL/TAL1) plays a key role in the development of murine primitive hematopoiesis but its functions in adult definitive hematopoiesis are still unclear. Using lentiviral delivery of TAL1-directed shRNA in human hematopoietic cells, we show that decreased expression of TAL1 induced major disorders at different levels of adult hematopoietic cell development. Erythroid and myeloid cell production in cultures was dramatically decreased in TAL1-directed shRNA- IntroductionStem cell leukemia/T cell acute leukemia 1 (SCL/TAL1) belongs to a group of nuclear factors called basic helix-loop-helix (bHLH) transcription factors. 1 During hematopoiesis, TAL1 is expressed mainly in erythroid cells, megakaryocytic cells, and hematopoietic stem cells (HSCs) 2,3 where it has been implicated in different steps of development and differentiation. 1 TAL1 can activate or repress transcription through TAL1 nuclear complexes containing transcriptional activators or repressors. 4 These TAL1 nuclear transcription complexes are bound to lineage-specific regulatory regions in immature hematopoietic progenitors and undergo dynamic changes as HSCs differentiate, indicating the importance of TAL1 in the regulation of hematopoietic-specific genes from HSCs to differentiated hematopoietic progenitors. [4][5][6] TAL1 is known to play a crucial role in the generation of blood cells during mouse embryonic development 7,8 and mouse Tal1 Ϫ/Ϫ embryonic stem cells fail to participate in hematopoiesis, even in a blastocyst environment, 9 a failure that is rescued by re-expressing TAL1 before the onset of hematopoiesis. 10 Whereas the role of TAL1 during adult erythropoiesis and megakaryopoiesis is well defined in humans and mice, [11][12][13][14] its implication in the self-renewal and differentiation of adult HSCs and primitive hematopoietic progenitor cells is highly controversial. Conditional deletion of TAL1 in adult bone marrow (BM) cells reveals that TAL1 is either required 15 or not 13 to reconstitute hematopoiesis of lethally irradiated mice and, when it is required, the exact TAL1-dependent stem cell population is not clearly defined. Indeed, whereas deletion of TAL1 in mouse seems to alter short-term (ST) repopulating cells, 15 enforced TAL1 expression improves the reconstitution ability of human long-term SCID-repopulating cells (LT-SRCs), possibly through their increased self-renewal. 16 These observations partly correlate with the effects of enforced TAL1 expression in mouse HSCs in transgenic mice or using retroviral gene expression where differentiation of TAL1-overexpressing primitive cells showed increased myelopoiesis. 17,18 However, in these mouse studies, the effect of enforced TAL1 expression on the HSC compartment was not investigated and remains to be explored.To address the physiologic role of TAL1 in the HSC compartment and to identify TAL1-dependent progenitors, we have developed an shRNA-based strategy that specifically targets human or mouse TAL1 transcripts. We show here, and for t...

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“…Chez l'adulte, malgré une longue controverse [2,3], le rôle de TAL1 dans les cellules souches hématopoïétiques (CSH) a été récemment confirmé : ce facteur de transcription assurerait le maintien des CSH en préservant leur quiescence [4] et/ou en limitant leur apoptose [5]. TAL1 participe aussi à la régulation moléculaire des différenciations érythroïde, mégaca-ryocytaire et granulo-monocytaire [1] et il n'est pas exprimé au cours des différenciations lymphocytaires T et B [6]. Sur le plan mécanistique, TAL1 régule la transcription de nombreux gènes codant des protéines impliquées dans la diffé-renciation, l'apoptose ou le cycle cellulaire en participant à la formation de complexes transcriptionnels contenant des protéines telles que GATA1, 2 ou 3, ldb1, LMO1/2 et un membre de la famille E2A [1].…”

Section: Tal1 Et Lal-tunclassified

Comment un suppresseur de tumeur se prend au jeu de la prolifération leucémique chez l’homme

et al. 2011

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SCL Expression at Critical Points in Human Hematopoietic Lineage Commitment

Cited by 32 publications

References 32 publications

Id1, but not Id3, directs long-term repopulating hematopoietic stem-cell maintenance

Id1, but not Id3, directs long-term repopulating hematopoietic stem-cell maintenance

Low SCL/TAL1 expression reveals its major role in adult hematopoietic myeloid progenitors and stem cells

Comment un suppresseur de tumeur se prend au jeu de la prolifération leucémique chez l’homme

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