IRX-related homeobox gene MKX is a novel oncogene in acute myeloid leukemia and multiple myeloma

ABSTRACT: Homeobox genes encode transcription factors which organize differentiation processes in cells and tissues including hematopoiesis. Recently, we have reported restricted physiological expression of TALE-class homeobox gene IRX1 in early myelopoiesis at the megakaryocyte-erythroid-progenitor stage and in early B-cell development at the pro-B-cell stage, while IRX3 and IRX5 are aberrantly activated in the corresponding malignancies acute myeloid leukemia (AML) and progenitor B-cell acute lymphoid leukemia. Here, we examined the role of IRX-related homeobox gene MKX (IRXL1 or mohawk) in normal and malignant hematopoiesis. Screening of 100 leukemia/lymphoma cell lines revealed MKX expression in AML and multiple myeloma (MM) derived cell lines. While MKX was silent in normal myelopoiesis and B-cell differentiation, aberrant activity was detected in subsets of AML and MM patients. To investigate its aberrant regulation and oncogenic function we used AML cell line OCI-AML3 as model which strongly expressed MKX at the RNA and protein level. IRX5, JUNB and NFkB activated MKX in this cell line while downregulated GATA2 and STAT5 inhibited its expression. MKX downstream analysis was performed by siRNA-mediated knockdown and RNA-sequencing in OCI-AML3, and by comparative expression profiling analysis of a public dataset from MM patients. The data revealed activation of CCL2 which in turn promoted proliferation, and downregulation of BCL2L11 and upregulation of SESN3 which together may underlie decreased etoposide-induced apoptosis. Furthermore, CEBPD and GATA2 play a role in myeloid differentiation and were deregulated by MKX. Collectively, our study identified MKX as novel aberrantly expressed homeobox gene in AML and MM, highlighting the function of IRX1 and IRX-related genes in myelopoiesis and B-cell development and in corresponding malignancies.

ORGANISM(S): Homo sapiens (human)

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PROVIDER: S-BSST1315 | biostudies-other |

REPOSITORIES: biostudies-other