Transcriptional regulation in myelopoiesis: Hematopoietic fate choice, myeloid differentiation, and leukemogenesis

C/EBPA gene mutation and C/EBPA promoter hypermethylation in acute myeloid leukemia with normal cytogenetics

“…Interestingly, all seven patients with C/EBPA promoter hypermethylation did not show coexistence with C/EBPA mutation, suggesting C/EBPA gene mutation and promoter hypermethylation to appear mutually exclusive (Table II). Discussion C/EBPA is a critical regulator of hematopoietic stem cell (HSC) homeostasis and myeloid differentiation, and multiple studies have shown that C/EBPA function is frequently abrogated in AML [2][3][4]. Three mechanisms of C/EBPA inactivation have been reported: (1) downregulation of C/EBPA expression consecutive to the AML1-ETO fusion transcript in t(8,21) leukemia cells, interestingly conditional expression of C/EBPA in these cells is sufficient to trigger granulocytic differentiation [9]; (2) Suppression of C/EBPA function through inhibition of the translation of C/EBPA mRNA by interaction with hnRNPE2, which is induced by BCR-ABL; This mechanism could explain transition of chronic phase to myeloid blast crisis in CML by blocking myeloid differentiation [21], and (3) other genetic abnormalities affecting C/EBPA gene, particularly mutations, which have been reported in hematological malignancies, mainly in AML [22].…”

“…The CCAAT enhancer binding protein alpha (C/EBPA) is the founding member of the family of related leucine zipper transcription factors and plays an important role in numerous cellular processes including proliferation, differentiation, apoptosis, control of metabolism, and other specific functions [2][3][4]. Growing evidence indicates that the key function of C/EBPA gene can be altered by a number of mechanisms, such as gene mutation, transcriptional dysregulation, as well as epigenetic modification in leukemic cells of AML patients, and the functional inactivation of C/EBPA has become a pathophysiological signature of myeloid leukemia.…”

Transcriptional dysregulation during myeloid transformation in AML

“…Although the ultimate relationship between altered proliferation and differentiation in AML remains to be resolved, recent evidence suggests a concept in which disruption of some transcription factors critically affects both cell cycle and differentiation as being important in AML. Whereas the transcriptional control of normal myeloid development has recently been extensively summarized (Friedman, 2002;Rosmarin et al, 2005;Mueller and Pabst, 2006;Rosenbauer and Tenen, 2007), as well as elsewhere in this issue, this review intends to highlight aspects of transcriptional dysregulation in human AML. The focus is on the transcription factors CCAAT/enhancer binding protein-a (CEBPA), PU.1 and RUNX1.…”

“…The main role of CEBPA in hematopoiesis is in the development of granulocytes Friedman, 2002;Tenen, 2003;Rosmarin et al, 2005). Nonconditional targeted disruption of CEBPA results in a selective block in early granulocyte maturation .…”

Phosphatidylinositol 3-kinase/Akt signaling mediates interleukin-6 protection against p53-induced apoptosis in M1 myeloid leukemic cells

“…Aberrations in the complex cytokine and transcription factor network that regulate hematopoiesis lead to hematological disorders (Liebermann et al, 1995;Moqattash et al, 1998;Zhu et al, 2002;Tenen, 2003;Rosmarin et al, 2005). The myeloid cell compartment provides an excellent model to study molecular processes associated with homeostasis of blood cells, including cellular proliferation, survival and programmed cell death (i.e., apoptosis) and how aberrations in these processes result in oncogenesis .…”