Dr. Bandana Ajay Vishwakarma, a Ph.D. graduate from Uniformed Services University of the Health Sciences in Bethesda, Md., recently demonstrated through her study that SET binding protein 1 induces myeloid leukemia in mice.
SETBP1 does this by repressing a critical hematopoiesis regulator gene Runx1 by recruiting NuRD complex and HDAC inhibitors that could be potential molecules for treating myeloid malignancies with SETBP1 activation.
Vishwakarma conducted her research under the guidance of Dr. Yang Du at USUHS’ Department of Pediatrics. SETBP1, a recently discovered oncogene, is found to be over-expressed in elderly patients of acute myeloid leukemia and in blast crisis of chronic myeloid leukemia. Activation mutation of SETBP1 has also been reported in multiple myeloid malignancies.
It was first identified as an interaction partner of SET. Vishwakarma and her co-investigators from Du’s lab showed that it is an AT-Hook transcription factor and activates oncogenes Hoxa9 and Hoxa10. It also promotes a self-renewal capability to myeloid progenitors both in-vitro and in-vivo.
The over-expression of SETBP1 in 5-Fluorouracil treated bone marrow cells increased the self-renewal capacity of hematopoietic stem cells and caused expansion of granulocytes macrophage progenitors. The novelty of the work is the demonstration of the oncogenic capability of Setbp1 through the transcriptional repression of tumor suppressor gene Runx1.
HDAC inhibitors could be a promising strategy in the treatment of myeloid leukemia with SETBP1 over-expression or mutation, as it could relieve the repression of Runx1 and prolong survival in mice.
The research has been published in the January 2016 issue of the journal Leukemia.