Pediatrics Leukemia Research
Leukemia Research

 

THE PROBLEM

The long-term goal of this work is to understand the mechanisms underlying leukemia development and to identify better molecular targets for leukemia therapy. The primary research interest is to study the self-renewal mechanisms of leukemia stem cells whose elimination is essential for curing leukemia.

OUR APPROACH

The laboratory has been focusing on the gene for SETBP1 since 2009, and its studies have contributed significantly to the establishment of SETBP1 as a critical regulator of leukemic stem cell self-renewal in myeloid leukemias.

LEAD FACULTY

Yang (Dennis) Du
 

Innovations & Discoveries

This lab was the first to demonstrate that SETBP1 activation is capable of conferring self-renewal capability to myeloid progenitors in vitro and in vivo. Studies from the lab also showed for the first time that SETBP1 is a transcription factor capable of both activating and repressing gene transcription dependent on promoter context and identified a number of oncogenic transcription factor genes including Hoxa9/Hoxa10/Myb, ribosomal protein genes, and tumor suppressor gene Runx1 as its direct transcriptional targets.

The lab discovered histone deacetylase (HDAC) inhibition as a promising strategy for treating myeloid leukemia patients with SETBP1 overexpression. Most significantly, to document the importance of the role of SETBP1 gene in human leukemia development, this lab and its collaborators were first to describe highly recurrent activating missense mutations of SETBP1 present in chronic myelomonocytic leukemia (CMML) and secondary acute myeloid leukemia (sAML), and myelodysplastic syndrome (MDS), suggesting that SETBP1 activation is a major contributor to the development of myeloid neoplasms. More recently, the lab has also established XPO1 and MLL1 (KMT2A) as essential cofactors for SETBP1 and its missense mutants to induce transcriptional activation.

LOOKING AHEAD

For future studies, the focus will be on better understanding the epigenetic mechanisms responsible for target gene activation and repression induced by SETBP1. In summary, the work done in this laboratory has contributed significantly to the field of leukemia research, especially with the establishment of SETBP1 as a significant oncogene in the development of human myeloid neoplasms. The focus will continue to be on understanding the molecular mechanisms for its role in regulating LSC self-renewal and identifying effective therapeutic strategies for leukemias induced by its activation.

 

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