Chronic myelomonocytic leukemia (CMML) is a devastating cancer for which there is currently no effective therapy. Approximately 30% of CMML cases evolve to acute myelogenous leukemia AML soon after their initial diagnosis, contributing to the high morbidity and mortality (median survival: ~20 months). While recent sequencing efforts have identified numerous somatic mutations in CMML, little is known about the genetic predisposition of individuals to develop CMML. We recently reported an ASXL1/NRAS mutated CMML that occurred in an individual with a germline ANKRD26 variant familial thrombocytopenia syndrome, suggesting that previously unrecognized germline sequence variants (GSVs) may predispose patients to develop CMML and work cooperatively with somatic mutations (e.g. RAS pathway mutations) to promote disease progression (including transformation to AML). Consistent with this idea, we have identified two recurrent GSVs in the TCOF1 gene with much higher frequency in CMML patients than those in the normal population. Both GSVs change the nucleolar localization of wild-type TCOF1 protein and may partially inhibit WT TCOF1 function. Downregulating Tcof1 in vivo not only induced CMML-like phenotypes in a fraction of mice but also significantly shortened the survival of NrasQ61R/+ mice. Based on our preliminary data, we hypothesize that TCOF1 GSVs confer an increased risk for the development of CMML and genetically interact with somatic mutations (e.g. oncogenic RAS mutations and/or ASXL1 mutations) to drive CMML progression. We propose the following two specific aims to test our hypothesis: 1) To investigate whether TCOF1 GSVs confer an increased risk of CMML development and whether they associate with specific somatic mutations to promote CMML progression; 2) To establish leukemia cell lines and mouse model with targeted TCOF1 GSVs. Successful accomplishment of the proposed studies will not only provide fundamental perspectives on disease predisposition and genetic interactions between GSVs and somatic mutations, but also generate powerful tools for future mechanistic and translational research in the CMML field.

Public Health Relevance

Chronic myelomonocytic leukemia (CMML) is a devastating disease that primarily affects the elderly. Although we have started to understand how somatic mutations initiate CMML and drive its progression, little is known about CMML-relevant germline sequence variants (GSVs). Do GSVs affect predisposition to CMML? Do they cooperate with somatic mutations to promote CMML progression and/or a differential response to therapy? If the answers are yes, then what are the mechanisms underlying these interactions? These are the important questions that we aim to address in this proposal. This application directly addresses the Provocative Question (PQ) #3: Do genetic interactions between germline variations and somatic mutations contribute to differences in tumor evolution or response to therapy?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA152108-08S1
Application #
9731181
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Duglas Tabor, Yvonne
Project Start
2011-09-02
Project End
2021-03-31
Budget Start
2019-04-03
Budget End
2020-03-31
Support Year
8
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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