Juvenile myelomonocytic leukemia (JMML) is a malignant blood disorder of childhood associated with a dismal prognosis. The hallmark of JMML is aberrant signaling through the Ras pathway caused by mutations in NF1, NRAS, KRAS, PTPN11 and CBL. The current standard of care involves hematopoietic stem cell transplantation (HSCT), yet only 50% of patients are cured of their disease. Prior to our report on the presence of subclonal SETBP1 mutations detected using droplet digital PCR (ddPCR) and our recently published exome sequencing findings, there have been no reliable predictors of outcome in this disease. SETBP1 mutations have also been identified in acute myeloid leukemia (AML), secondary AML, myelodysplastic syndrome (MDS), secondary MDS, chronic myelomonocytic leukemia, and atypical chronic myeloid leukemia. While the exact function of SETBP1 has yet to be elucidated, it was initially discovered as an inhibitor of the tumor suppressor protein phosphatase 2 (PP2A). Data from AML indicates that SETBP1 mutations confer self-renewal properties to myeloid progenitor cells via up regulation of HOX genes. However the exact mechanisms underpinning SETBP1 mediated leukemogenesis are largely unknown and there are no drugs available to specifically target SETBP1. The goal of this proposal is to identify compounds that will be effective in treating patients with SETBP1 driven leukemia. I have measured RNA expression levels of 800 cancer related genes using the nCounter platform in JMML patients with and without SETBP1 mutations, which revealed significant up-regulation of three histone- related genes in patients with SETBP1 mutations.
In Aim 1 of this proposal, I will be testing compounds predicted to affect histone and HOX related genes, alone and in combination. These experiments will be performed in cell lines with SETBP1 mutations as well as cells from patients with SETBP1 mutations.
In Aim 2, I will be carrying out a genome wide screen to look for other genes that are necessary for SETBP1 to function. This will help identify targets so that I can rationally pick additional compounds that would be predicted to be effective. The goal of both aims would be to identify combinatorial treatments to help improve outcomes for patients with SETBP1 mutations.

Public Health Relevance

Myeloproliferative neoplasms are a type of leukemia that can occur in children or adults and are frequently difficult to treat. Specifically when leukemias have a mutation in a gene called SETBP1, they become particularly difficult to cure but we don't currently understand why. My research will use cutting edge technologies to answer this question and pinpoint treatments for patients with SETBP1 driven leukemia.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
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Special Emphasis Panel (ZHL1)
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Welniak, Lisbeth A
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Stieglitz, Elliot; Mazor, Tali; Olshen, Adam B et al. (2017) Genome-wide DNA methylation is predictive of outcome in juvenile myelomonocytic leukemia. Nat Commun 8:2127