C/EBPα and MYB regulate FLT3 expression in AML

Abstract

The interaction between the receptor FLT3 (FMS-like tyrosine kinase-3) and its ligand FL leads to crucial signalling during the early stages of the commitment of haematopoietic stem cells. Mutation or over-expression of the FLT3 gene, leading to constitutive signalling, enhances the survival and expansion of a variety of leukaemias and is associated with an unfavourable clinical outcome for acute myeloid leukaemia (AML) patients. In this study, we used a murine cellular model for AML and primary leukaemic cells from AML patients to investigate the molecular mechanisms underlying the regulation of FLT3 gene expression and identify its key cis-and transregulators. By assessing DNA accessibility and epigenetic markings, we defined regulatory domains in the FLT3 promoter and first intron. These elements permit in vivo binding of several AML-related transcription factors, including the proto-oncogene MYB and the CCAAT/enhancer binding protein C/EBPα, which are recruited to the FLT3 promoter and intronic module, respectively. Substantiating their relevance to the human disease, our analysis of gene expression profiling arrays from AML patients uncovered significant correlations between FLT3 expression level and that of MYB and CEBPA. The latter relationship permits discrimination between patients with CEBPA mono-and bi-allelic mutations, and thus connects two major prognostic factors for AML.

AMKL chimeric transcription factors are potent inducers of leukemia

“…NIPBL-HOXB9, GATA2-HOXA9 , and MN1-FLI1 leukemias all up-regulated Flt3 when compared to normal myeloid progenitors (Supplementary Figure S12C, Table S6). The promoter/enhancer region of Flt3 contains ETS, HOX and GATA binding sites, providing a rationale for the ability of the three different fusion genes to uniformly increase Flt3 expression(43, 44). …”

RNA binding protein MSI2 positively regulates FLT3 expression in myeloid leukemia

“…Consistent with this idea, homeobox transcription factors, such as HOXA9, PBX3 and MEIS1, cooperate to activate FLT3 mRNA transcription and are capable of inducing de novo AMLs when overexpressed [47–51]. The bZIP transcription factor CEBPα and the proto-oncogene c-Myb have also been implicated in the FLT3 transcriptional activation in AML [52]. These previous studies clearly demonstrated that aberrant FLT3 activation mediates leukemogenesis triggered by oncogenic transcription factors.…”

Dysregulation of c-Myb Pathway by Aberrant Expression of Proto-oncogene MYB Provides the Basis for Malignancy in Adult T-cell Leukemia/lymphoma Cells

“…We have demonstrated increases in the expression of not only overall c-Myb but also of c-Myb-9A, an isoform with a "gain -of-function oncogenic characteristics," in ATL cells. In tumors, MYB gene overexpression and its influence on cellular homeo-stasis have been extensively studied (27)(28)(29)(30)(31)(32)(33)(34)(35). Conversely, limited information is available regarding the expression profiles of c-Myb isoforms, each of which possesses a considerably different transactivation capacity and transforming activity.…”