Abstract
The proto-oncogenic protein c-Myb is an essential regulator of hematopoiesis and is frequently deregulated in hematological diseases such as lymphoma and leukemia. To gain insight into the mechanisms underlying the aberrant expression of c-Myb in myeloid leukemia, we analyzed and compared c-myb gene transcriptional regulation using two cell lines modeling normal hematopoietic progenitor cells (HPCs) and transformed myelomonocytic blasts. We report that the transcription factors HoxA9, Meis1, Pbx1 and Pbx2 bind in vivo to the c-myb locus and maintain its expression through different mechanisms in HPCs and leukemic cells. Our analysis also points to a critical role for Pbx2 in deregulating c-myb expression in murine myeloid cells cotransformed by the cooperative activity of HoxA9 and Meis1. This effect is associated with an intronic positioning of epigenetic marks and RNA polymerase II binding in the orthologous region of a previously described alternative promoter for c-myb. Taken together, our results could provide a first hint to explain the abnormal expression of c-myb in leukemic cells.
Highlights
C-Myb is a key regulator of hematopoiesis, influencing aspects of proliferation, differentiation and programmed cell death throughout the hematopoietic hierarchy
Aberrant c-Myb expression has been circumstantially associated with the development of several types of leukemia including chronic myeloid leukemia, acute lymphoblastic leukemia and acute myeloid leukemia (AML)
High levels of c-myb transcripts have been directly related to chromosomal translocation or duplication affecting the c-myb locus in subsets of acute lymphoblastic leukemia,[14,15] the mechanisms underlying abnormal expression of c-myb in chronic myeloid leukemia or AML remain unclear
Summary
C-Myb is a key regulator of hematopoiesis, influencing aspects of proliferation, differentiation and programmed cell death throughout the hematopoietic hierarchy. The Hox proteins represent a family of transcription factors containing a DNA-binding motif of 60 amino acids known as the homeodomain In addition to their role in embryonic development,[17] considerable evidence shows the importance of HoxA proteins as key regulators of hematopoiesis. The HPC7 line is a nonleukemic HPC line ectopically expressing the LIM-homeodomain protein Lhx[2], which retains multilineage differentiation capacity in response to specific cytokines.[24] Importantly, the Lhx[2] protein, which allows culture and expansion of the cells in an undifferentiated state, has been shown not to alter HPC properties.[25] We used the FMH9 line, derived from primary HoxA9/Meis1-transformed bone marrow progenitors, as an AML model. This rating of nuclease digestion highlighted the presence of several sites of hypersensitivity in the promoter (HS-B) and first intron (HS-C and HS-D), each encompassing a number of consensus sites for the binding of Hox c-myb observed in leukemic cells
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