Transgene Insertion in Proximity to the c-<i>myb</i> Gene Disrupts Erythroid-Megakaryocytic Lineage Bifurcation

Mukai, Harumi Y.; Motohashi, Hozumi; Onodera, Osamu; Suzuki, Norio; Nagano, Masumi; Yamamoto, Masayuki

doi:10.1128/mcb.00718-06

Cited by 66 publications

(55 citation statements)

References 37 publications

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“…A fortuitous genetic disruption of an upstream enhancer by transgene insertion resulted in a hypomorphic level of c-myb expression that led to an increase in megakaryocytes and a decrease in erythroid cells, 65 a result foreshadowed by an earlier knockdown study. 66 Known molecular properties of EKLF suggest at least 2 ways in which it could affect these bipotential decisions as an activator or as a repressor.…”

Section: Novel Role For Eklf In Lineage Commitment 3877mentioning

confidence: 67%

Novel role for EKLF in megakaryocyte lineage commitment

Frontelo

Manwani

Galdass

et al. 2007

Blood

129

168

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Megakaryocytes and erythroid cells are thought to derive from a common progenitor during hematopoietic differentiation. Although a number of transcriptional regulators are important for this process, they do not explain the bipotential result. We now show by gain-and loss-offunction studies that erythroid Krü ppellike factor (EKLF), a transcription factor whose role in erythroid gene regulation is well established, plays an unexpected directive role in the megakaryocyte lineage. EKLF inhibits the formation of megakaryocytes while at the same time stimulating erythroid differentiation. Quantitative examination of expression during hematopoiesis shows that, unlike genes whose presence is required for establishment of both lineages, EKLF is uniquely down-regulated in megakaryocytes after formation of the megakaryocyte-erythroid progenitor. Expression profiling and molecular analyses support these observations and suggest that megakaryocytic inhibition is achieved, at least in part, by EKLF repression of Fli-1 message levels. IntroductionHematopoiesis is the process by which a self-renewing population of stem cells provide a continuous replenishment of differentiated blood cells by generating progeny with sequentially altered gene expression patterns. [1][2][3] Identification of these cells has relied on selective enrichment by cell-surface markers combined with culture and in vivo cellular assays that enable detection of cells at specific stages of differentiation. Although stem cells are multipotent, individual steps of subsequent differentiative decisions are performed by a series of simpler, even bipotential, decisions whereby one cell type gives rise to 2 or 3 descendants of differing character. 4 This has led to a commonly accepted pattern of parent and progeny relations, 2 although variations of it have recently been suggested 5 (but see Forsberg et al 6 ).A large number of genetic, cellular, and gene expression studies point to the critical importance of cytokine pathways 7 and expression patterns of transcription factors 1,[8][9][10] for establishing and maintaining steady state numbers of lymphoid, myeloid, and erythroid cells that, at the same time, can respond quickly to changes in the organismal environment and increase or decrease the cellularity of specific blood cell types. The megakaryocyte and erythrocyte lineages are proposed to derive from a common precursor, the megakaryocyte-erythroid progenitor (MEP) 4,11,12 (reviewed in Pang et al 13 ). Strikingly, these 2 lineages share a number of commonalities with respect to transcription factors that are absolutely required (eg, GATA1,14,15 FOG1, 16 SCL,17, ). At the same time, the protein partners that form with these factors as differentiation proceeds can be significantly different between lineages. 20 However, because these factors are all positively required for both lineages, we are still left with an incomplete picture of how these lineages are differentially established during hematopoiesis. 13 Erythroid Krüppel-like factor (EKLF; KLF1 21 ) is ...

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Section: Novel Role For Eklf In Lineage Commitment 3877mentioning

confidence: 67%

Novel role for EKLF in megakaryocyte lineage commitment

Frontelo

Manwani

Galdass

et al. 2007

Blood

129

168

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“…13 No differential requirement of these factors for either lineage has been reported to date. In contrast, low levels of c-Myb favor megakaryocytic at the expense of erythrocytic lineage, 14 whereas the same is true for Stat5. 15 Aml1/Runx1 cooperates with Gata1 to activate some megakaryocytic promoters, 16 and conditional inactivation of Runx1 gene in adult inhibits megakaryocytic maturation but has no effect on erythrocytic differentiation.…”

Section: Introductionmentioning

confidence: 73%

Inducible Fli-1 gene deletion in adult mice modifies several myeloid lineage commitment decisions and accelerates proliferation arrest and terminal erythrocytic differentiation

Starck

Weiss‐Gayet

Gonnet

et al. 2010

Blood

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This study investigated the role of the ETS transcription factor Fli-1 in adult myelopoiesis using new transgenic mice allowing inducible Fli-1 gene deletion. Fli-1 deletion in adult induced mild thrombocytopenia associated with a drastic decrease in large mature megakaryocytes number. Bone marrow bipotent megakaryocyticerythrocytic progenitors (MEPs) increased by 50% without increase in erythrocytic and megakaryocytic common myeloid progenitor progeny, suggesting increased production from upstream stem cells. These MEPs were almost unable to generate pure colonies containing large mature megakaryocytes, but generated the same total number of colonies mainly identifiable as erythroid colonies containing a reduced number of more differentiated cells. Cytological and fluorescenceactivated cell sorting analyses of MEP progeny in semisolid and liquid cultures confirmed the drastic decrease in large mature megakaryocytes but revealed a surprisingly modest (50%) reduction of CD41-positive cells indicating the persistence of a megakaryocytic commitment potential. Symmetrical increase and decrease of monocytic and granulocytic progenitors were also observed in the progeny of purified granulocytic-monocytic progenitors and common myeloid progenitors. In summary, this study indicates that Fli-1 controls several lineages commitment decisions at the stem cell, MEP, and granulocytic-monocytic progenitor levels, stimulates the proliferation of committed erythrocytic progenitors at the expense of their differentiation, and is a major regulator of late stages of megakaryocytic differentiation. (Blood. 2010;116(23):4795-4805) IntroductionMature blood cells in adults are permanently regenerated from a limited pool of pluripotent hematopoietic stem cells (HSCs) localized in the bone marrow. This process occurs through the hierarchical generation of intermediate progenitors with more and more restricted differentiation and proliferation potential that can be prospectively purified. According to current models, myeloid lineages are derived from a common myeloid progenitor (CMP) generating 2 distinct bipotent progenitors, the megakaryocyticerythrocytic progenitors (MEPs) and the granulocytic-monocytic progenitors (GMP). 1 MEPs generate in turn erythrocytic and megakaryocytic monopotent progenitors, whereas GMP generate granulocytic and monocytic monopotent progenitors. Increasing data also indicate an alternative pathway generating MEPs directly from HSCs. [2][3][4] All this process is controlled by permanent crosstalk between extracellular signals and intracellular regulatory networks of transcription factors. Although having no instructive role, erythropoietin (EPO) is the major cytokine controlling erythropoiesis through the stimulation of proliferation and survival of committed erythrocytic progenitors expressing the specific receptor EPOR. 5 Thrombopoietin (TPO) is the major cytokine controlling megakaryopoiesis through the stimulation of proliferation and differentiation of committed megakaryocytic progenitors expressing the sp...

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“…Understanding the mechanism of action by which these variants result in alterations in HbF levels is important, as the genetic variants at this locus appear to have as great or perhaps even a greater effect on clinical morbidity in the b-hemoglobinopathies as those variants at the BCL11A locus (Galanello et al 2009;Nuinoon et al 2010). Interestingly, this region contains a variety of regulatory elements that have been suggested to have an important role in regulating expression of MYB in erythroid progenitors (Mukai et al 2006;Wahlberg et al 2009;Stadhouders et al 2011). Although overexpression of HBS1L did not appear to effect g-globin expression in K562 erythroleukemia cells, overexpression of MYB did appear to affect the level of g-globin produced in these cells (Jiang et al 2006).…”

Section: Switch From Fetal To Adult Hemoglobinmentioning

confidence: 99%

The Switch from Fetal to Adult Hemoglobin

Sankaran

Orkin

2012

Cold Spring Harbor Perspectives in Medicine

249

178

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The fetal-to-adult hemoglobin switch and silencing of fetal hemoglobin (HbF) have been areas of long-standing interest among hematologists, given the fact that clinical induction of HbF production holds tremendous promise to ameliorate the clinical symptoms of sickle cell disease (SCD) and b-thalassemia. In this article, we discuss historic attempts to induce HbF that have resulted in some therapeutic approaches to manage SCD and b-thalassemia. We then go on to discuss how more recent molecular studies that have identified regulators, including BCL11A, MYB, and KLF1, hold great promise to develop targeted and more effective approaches for HbF induction. We go on to discuss strategies by which such approaches may be developed. Older studies in this field can provide important lessons for future studies aimed at developing more effective strategies for HbF induction, and we therefore chronologically cover the work accomplished as this field has evolved over the course of the past four decades.A s with many facets of the history of the hemoglobin field, the study of the fetal-toadult hemoglobin switch and work on fetal hemoglobin silencing has a rich and storied history that spans the course of several decades. In this work, we begin with a historic overview of this field and then move on to discuss more recent molecular findings that are providing important new insight into this process. There is great hope that these new molecular studies may lead to important targeted therapeutic advances for fetal hemoglobin (HbF) induction. However, the historic work in this field suggests that the road to effective therapies may not always be straightforward and reconsidering seemingly simple observations can often yield important new insights. There are many valuable lessons that can be learned from both the historic and more recent work in this field and therefore we attempt to cover the chronology of findings that have resulted in our current understanding of the fetal-to-adult hemoglobin switch.The disorders of b-hemoglobin, sickle cell disease (SCD) and b-thalassemia, are major sources of morbidity and mortality worldwide (Weatherall et al. 2006). These diseases are the

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Transgene Insertion in Proximity to the c-myb Gene Disrupts Erythroid-Megakaryocytic Lineage Bifurcation

Cited by 66 publications

References 37 publications

Novel role for EKLF in megakaryocyte lineage commitment

Novel role for EKLF in megakaryocyte lineage commitment

Inducible Fli-1 gene deletion in adult mice modifies several myeloid lineage commitment decisions and accelerates proliferation arrest and terminal erythrocytic differentiation

The Switch from Fetal to Adult Hemoglobin

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