Cooperation of Setbp1 with BCR/ABL in Development of CML Myeloid Blast Crisis
Abstract
Mechanisms underlying the progression of Chronic Myeloid Leukemia (CML), primarily induced by BCR/ABL translocation, from chronic phase to blast crisis are poorly understood. Our laboratory has previously shown that SETBP1 activation contributes to this progression by conferring unlimited self-renewal capability to granulocyte macrophage progenitors (GMPs). Here I show that overexpression of Hoxa9 or Hoxa10 alone, both transcriptional target of Setbp1 is able to promote self-renewal of primary myeloid progenitors in vitro in the presence of stem cell factor (SCF) and interleukin-3 (IL-3). In addition, similar to Setbp1, Hoxa9 or Hoxa10 is able to cooperate with BCR/ABL to induce development of aggressive leukemias which resemble CML myeloid blast crisis from GMPs. I further identify Myb as a critical downstream target of Hoxa9 and Hoxa10, as Myb knockdown significantly reduced colony-forming potential of myeloid progenitors immortalized by Hoxa9 and Hoxa10. Interestingly, ectopic expression of Myb efficiently immortalized primary myeloid progenitors in culture and was also capable of cooperating with BCR/ABL to induce leukemic transformation of GMPs in mice. These results suggest that activation of Myb is a critical downstream event of Setbp1/Hoxa9/Hoxa10 activation in their cooperation with BCR/ABL to induce CML blast crisis transformation. Therefore, Myb may represent a promising therapeutic target for treating CML blast crisis.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 09, 2016
- Accession Number
- AD1127810
Entities
People
- Vijay Negi
Organizations
- Uniformed Services University of the Health Sciences