The leucine zipper region of Myb oncoprotein regulates the commitment of hematopoietic progenitors

Abstract

IntroductionDifferentiation of hematopoietic stem cells and progenitors into various lineages is controlled by a complex array of extrinsic and intrinsic factors. [1][2][3][4] Myeloid and erythroid blood cells develop from a common myeloid progenitor, which differentiates into either megakaryocytes and erythrocytes, or granulocytes and macrophages. Several experimental strategies including gene targeting, expression pattern analysis, antisense, and overexpression studies led to the identification of transcription factors that are required for formation, survival, and proliferation of multilineage progenitors and that direct the differentiation and maturation of individual lineages. Specifically, factors like SCL, Rbtn2, GATA-2, and c-Myb were found to be essential for multipotent cells. 5 In more mature cells, the expression of SCL, GATA-1, c-Myb, Rbtn2, FOG, and EKLF is a prerequisite for proper development of the erythroid lineage. On the other hand, factors of the C/EBP family, PU.1, Egr-1, c-Myb, and AML-1 play an important role in the myeloid lineage. [6][7][8][9] It has been suggested that in the common myeloid progenitor the concentrations of intracellular lineage-determining regulators are to be low and balanced. 10,11 During the commitment process this balance is disturbed either in a stochastic or instructed manner, resulting in the prevalence of a particular set of factors and the subsequent development of the respective lineage. Several factors were identified that instruct progenitor cells to develop along a specific lineage. Using the model of primary chicken myb-etstransformed multipotent progenitors (MEP), 12 it was demonstrated that PU.1 and C/EBP␤ forced differentiation of MEP progenitors into myeloid cells, and C/EBP␣ only into eosinophils. 13,14 In mammalian cells, Egr-1 was found to commit myeloid cells into the macrophage lineage with the concomitant block to differentiation into granulocytes. 15 The c-myb proto-oncogene is essential for early definitive myeloid and erythroid cells as documented by gene targeting experiments. 16 It is required for the expansion of immature cells of the myeloid, erythroid, and lymphoid lineages and is downregulated during their terminal differentiations. 17 The v-myb gene transduced by avian myeloblastosis virus (AMV), as well as its truncated homologue, transduced as the myb-ets fusion by E26 leukemia virus, are oncogenes that specifically affect the developmental programs of avian hematopoietic cells. AMV v-Myb interferes exclusively with the development of the macrophage lineage of both primitive and definitive hematopoietic cells by blocking terminal differentiation of macrophage precursors and activating their self-renewal capacities in vitro. It causes fatal acute monoblastic leukemia in chicks. E26 v-Myb-Ets fusion protein transforms multipotent progenitors of primitive hematopoietic cells (blastoderm), and committed erythroid and myeloid cells of bone marrow. It induces erythroid leukemia in infected chicks. [18][19][20][21][22] Thus, the E26 v-Myb-E...

A functional SUMO-interacting motif in the transactivation domain of c-Myb regulates its myeloid transforming ability

“…The second explanation would potentially substantiate the hypothesis of a fold-back mechanism involving the EVES domain and the N-terminal region in c-Myb (Dash et al, 1996;Karafiat et al, 2001) or the transactivation domain (Dubendorff et al, 1992;Vorbrueggen et al, 1994). Such intramolecular interactions have been hypothesized to conceal co-activator binding epitopes, thus lowering c-Myb activity.…”

Identification of CD13+CD36+ cells as a common progenitor for erythroid and myeloid lineages in human bone marrow

“…The colony-forming experiments further demonstrate this bi-directional differentiation potential. Co-expression of CD13 and CD36 antigens might reflect the intracellular overlap or balance of transcription factors, such as C/EBPa [7], GATA-1 and PU.1 [29], or other lineage switch-related genes, such as Myb LZR [30] and glia maturation factor gamma [15] although the molecular mechanisms controlling erythroid and myeloid commitment are largely unknown. These transcription factors or genes may function as a base on these cells of possessing bi-potential differentiation for their fate conversion (switching) or lineage plasticity in normal hematopoiesis.…”

E26 leukemia virus converts primitive erythroid cells into cycling multilineage progenitors

“…Each domain of the oncoprotein, if expressed on its own, is sufficient to induce the proliferation of erythroid cells in culture. 44,45 When expressed together, they cooperate in inducing erythroid cell proliferation 44 but they need to be fused to induce an MEP phenotype. 17 An interesting possibility is that Myb-Ets forces a transition from primitive-to-definitive hematopoietic cells by mimicking a process that is exerted by c-Myb during normal development.…”