Functional but Abnormal Adult Erythropoiesis in the Absence of the Stem Cell Leukemia Gene

Hall, Mark; Slater, Nicholas J.; Begley, C. Glenn; Salmon, Jessica M.; Stekelenburg, Leonie J. Van; McCormack, Matthew P.; Jane, Stephen M.; Curtis, David J.

doi:10.1128/mcb.25.15.6355-6362.2005

Cited by 46 publications

(53 citation statements)

References 41 publications

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“…These data showed that HSC development and function is not dependent on SCL expression once specification of the hematopoietic fate in the early embryo has been achieved. Yet, SCL remains essential for maintaining proper differentiation of primitive and definitive erythroid and megakaryocyte lineage cells in the yolk sac, fetal liver, and bone marrow (15,17,18). These findings contradict existing paradigms of lineage specification, in which continuous expression of the transcription factor that specifies a lineage is required to maintain the lineage, and suggests that SCLinduced hematopoietic specification is a stable cell fate that is not challenged with loss of SCL later on in development.…”

Section: Commitment To the Hematopoietic Fatecontrasting

confidence: 54%

Transcriptional Activators, Repressors, and Epigenetic Modifiers Controlling Hematopoietic Stem Cell Development

Teitell

Mikkola

2006

Pediatr Res

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Hematopoietic stem cells (HSCs) are pluripotent cells that give rise to all of the circulating blood cell types. Their unique ability to self-renew while generating differentiated daughter cells permits HSCs to sustain blood cell production throughout life. In mammals, the pool of HSCs shifts from early sites in the aortagonad-mesonephros region and the placenta to the fetal liver and ultimately bone marrow. During the past decade, a map of transcriptional activators and repressors that regulate gene expression in HSCs, their precursors and their progeny, at distinct stages of development has been drafted. These factors control a program that first establishes the pool of HSCs in the fetus, and later guides decisions between quiescence, self-renewal, and lineage commitment with progressive differentiation to maintain homeostasis. Continuing studies of the regulatory mechanisms that control HSC gene expression followed by the identification of specific loci that are activated or silenced during the life of an HSC will help to further elucidate longstanding issues in HSC decisions to self-renew or to differentiate, and to define the origins of and connections between distinct HSC pools and their precursors. (Pediatr Res 59: 33R-39R, 2006)

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Section: Commitment To the Hematopoietic Fatecontrasting

confidence: 54%

Transcriptional Activators, Repressors, and Epigenetic Modifiers Controlling Hematopoietic Stem Cell Development

Teitell

Mikkola

2006

Pediatr Res

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“…A drop in cellular Ter119 expression was observed in addition to suppressed erythroid development in the bone marrow of LSD1-kd mice (Figure 4g). Interestingly, lower Ter119 expression is a feature of SCL-deficient erythropoiesis, 37 suggesting cooperation between SCL and LSD1 in regulating Ter119. Even more prominent was the decrease of CD105/endoglin-expression on LSD1-kd CFU-E progenitor cells.…”

Section: Resultsmentioning

confidence: 99%

Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation

Sprüssel¹,

Schulte²,

et al. 2012

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“…Like Gfi1b, TAL1/Scl is also required for embryonic hematopoiesis, but when it was deleted in adult mice, these mice were mildly anemic. While the bone marrow was defective in CFU-S assays, these mice had increased numbers of MEPs and normal percentages of CMPs and GMPs (10,21,22,42), whereas the Mtg16-null mice have fewer MEPs and an abnormal CD34 hi / Fc␥R low myeloid progenitor cell population ( Fig. 5 and 6).…”

Section: Discussionmentioning

confidence: 99%

Deletion of Mtg16, a Target of t(16;21), Alters Hematopoietic Progenitor Cell Proliferation and Lineage Allocation

Chyla¹,

Moreno–Miralles²,

Steapleton³

et al. 2008

Molecular and Cellular Biology

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Chromosomal translocations disrupt master regulatory genes that control cellular proliferation, apoptosis, and the lineage decisions of progenitor cells (25,53). Indeed, a critical component in the development of acute leukemia is the shunting of stem cells or multipotent progenitor cells toward a specific lineage, which also must acquire the ability to self-renew, to give rise to a specific form of acute myeloid leukemia (AML). The myeloid translocation gene on chromosome 16 (MTG16, also known as ETO-2 or CBFA2T3) and myeloid translocation gene on chromosome 8 (MTG8, also known as Eight-Twenty-one or ETO) are disrupted by t(16;21) and t(8;21), respectively. While t(8; 21) accounts for as much as 10 to 15% of de novo AML (11, 12, 16, 17, 30, 43, 44), t(16;21) is relatively rare. Yet, the analysis of genes involved in rare translocations is often highly informative (35). In addition to mutations in acute leukemia, MTG8 was identified as a candidate cancer gene in colorectal carcinoma and mutations in MTG16 were also found in the initial screen (59). Moreover, MTG16 may also be inactivated in breast cancer (31). Thus, the analysis of the normal physiological functions of the MTG family is critical to our understanding of the development of acute leukemia and how mutation of MTG family members contributes to tumorigenesis in other organ systems.The chromosomal translocation fusion proteins created at the breakpoints of t(8;21) and t(16;21) repress the transcription of tumor suppressor genes and genes that are required for hematopoietic differentiation (34). This is achieved by recruiting histone deacetylases and other transcriptional corepressors through their MTG8 or MTG16 sequences. Indeed, MTG family members associate with N-CoR/SMRT; mSin3A/3B; and histone deacetylases 1, 2, and 3 (2,18,23,36,63). MTG family members are recruited by DNA binding factors involved in chromosomal translocations (PLZF and BCL6) and by other regulators of hematopoiesis (e.g., TAL1/SCL, Gfi1, Gfi1b, and HEB) (9,20,39,40,55,68). Thus, the cumulative data suggest that the MTG/ETO family members function as transcriptional corepressors whose activities are coopted by chromosomal translocations to induce leukemia.Gene disruption strategies have been valuable to dissect the regulatory pathways and identify the critical factors that mediate the decision of a stem cell to self-renew and quiesce or to enter the rapidly expanding progenitor cell pool to populate the various hematopoietic cell lineages. Many of these key regulators are DNA binding transcription factors, which control gene expression programs to influence proliferation and differentiation. By contrast, only a limited number of the transcriptional regulators and chromatin remodeling factors that are recruited by DNA binding factors have been pinpointed as contributors to stem cell functions. This is especially true for transcriptional corepressors and gene silencing factors. Although a great deal of information has been gathered about the molecular interactions of the MTG famil...

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Functional but Abnormal Adult Erythropoiesis in the Absence of the Stem Cell Leukemia Gene

Cited by 46 publications

References 41 publications

Transcriptional Activators, Repressors, and Epigenetic Modifiers Controlling Hematopoietic Stem Cell Development

Transcriptional Activators, Repressors, and Epigenetic Modifiers Controlling Hematopoietic Stem Cell Development

Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation

Deletion of Mtg16, a Target of t(16;21), Alters Hematopoietic Progenitor Cell Proliferation and Lineage Allocation

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