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Distal regulation of c-myb expression in human myeloid leukemia cells

ABSTRACT: The transcription factor c-Myb a key regulator in proliferation and differentiation of hematopoietic progenitor cells, is precisely regulated during essential cellular processes. Overexpression and rearrangement of c-myb has been reported in human tumors including myeloid leukemia, but exact regulatory mechanisms have remained elusive. Here, we identified, using 4C assay with the c-myb promoter as an anchor, the interaction site at -34k region upstream of c-myb gene that are involved in c-myb expression. Furthermore, we found that the long-range interactions changed with c-myb being down-regulated on differentiation progress in human myeloid leukemia cell lines. Taken together, our date revealed that a potential c-myb enhancer-promoter interactions may be a particularly important regulatory mechanism for c-myb gene expression in human myeloid leukemia cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE140321 | GEO | 2020/11/13

REPOSITORIES: GEO

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Project description:The MYB oncogene is widely expressed in acute leukemias and is important for the continued proliferation of leukemia cells, raising the possibility that MYB may be a therapeutic target. However realization of this potential requires (i) a significant therapeutic window for MYB inhibition, given its essential role in normal hematopoiesis; and (ii) an approach for developing an effective therapeutic. We previously showed that the interaction of Myb with the coactivator CBP/p300 is essential for its transforming activity. Here we use hematopoietic cells from the Booreana mouse strain, which carries a mutation in Myb that prevents interaction with CBP/p300, to examine the requirement for this interaction in myeloid transformation and leukemogenesis. Using this strain and a strain (plt6) carrying a “complementary” mutation in p300, we show that the Myb-p300 interaction is essential for in vitro transformation by the myeloid leukemia oncogenes AML1-ETO, AML1-ETO9a, MLL-ENL, and MLL-AF9. We further show that unlike cells from wild-type (WT) mice, Booreana cells fail to induce leukemia upon transplantation into irradiated recipients following transduction with an AML1-ETO9a retrovirus. These data highlight disruption of the Myb-p300 interaction as a potential therapeutic strategy for AML and suggest that such a strategy would have a useable therapeutic index since Booreana mice, unlike Myb null mice, are viable. Finally we have begun to explore the molecular basis of the these observations by gene expression profiling; this highlighted several genes previously implicated in myeloid leukemogenesis as being differentially expressed between WT and Booreana cells transduced with AML1-ETO9a. Total RNA was obtained from FACS sorted GFP+;c-Kit+ primary bone marrow cells from WT and Booreana mouse strains which had been cultured for 48 hours post-transduction with Control or AML1-ETO9a retroviruses. RNA was extracted from each of 4 samples per group and used to probe Illumina mouse Beadchips array.

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Distal regulation of c-myb expression in human myeloid leukemia cells

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