Certain oncogenes that promote solid tumors, such as RAS and BRAF, induce senescence when expressed in primary cells. Oncogene-induced senescence plays an important role in suppressing tumorigenesis by preventing proliferation of cells at risk for neoplastic transformation. Thus, in many instances, genes involved in oncogene-induced senescence, such as TP53 and RB1, are also tumor suppressors. BCR-ABL is an oncogenic kinase derived from the translocation between chromosomes 9 and 22 that can transform myeloid progenitor cells and drives the development of the vast majority chronic myeloid leukemia (CML) cases and 20%-30% of adult acute lymphoblastic leukemia (ALL) cases. We have recently found that BCR-ABL, as well as two other leukemogenic fusion-proteins, CBFB-MYH11 and RUNX1-ETO, can, like RAS and BRAF, induce senescence in primary human fibroblasts and hematopoietic progenitors. Our results imply that the development of BCR-ABL+ leukemias involves genetic and/or epigenetic alterations that inactivate one or more senescence-promoting genes. Consistent with this hypothesis, inactivation of genes known to promote senescence, such as TP53 and CDKN2A (p16INK4a/p14ARF), can cooperate with BCR-ABL in mouse models of CML, and CDKN2A deletions are frequently found in patients with BCR-ABL+ ALL. Significantly, these same genetic alterations can also confer resistance to imatinib, an inhibitor of BCR-ABL kinase activity that is the first-line treatment for CML. Thus, delineating the genes and regulatory pathways by which BCR-ABL induces senescence in primary cells will help identify genetic alterations that cooperate with BCR-ABL to promote leukemogenesis and are responsible for the emergence of imatinib resistance. Toward this long-term objective, we have carried out a large-scale RNA interference screen to identify genes whose knockdown enables primary cells to overcome BCR-ABL-induced senescence. These genes represent candidate suppressors of BCR-ABL+ leukemias. In this application, we propose experiments involving both cultured cells and mouse models of CML and ALL to determine the role of these candidates in suppression of BCR-ABL+ leukemias. The confirmed leukemia suppressor genes will be further studied to gain insights into how they promote senescence and to identify the regulatory pathways in which they function. Finally, confirmed leukemia suppressor genes will be tested for a role in the development of resistance to imatinib as well as dasatinib, the major second-generation tyrosine kinase inhibitor. The results of these experiments will improve our understanding of BCR-ABL+ leukemia development, reveal potential new targets for therapeutic intervention, and help predict patient responsiveness to treatment.

Public Health Relevance

Approximately 95% of chronic myeloid leukemias and 20-30% of adult acute lymphoblastic leukemias are caused by a specific chromosomal abnormality that fuses two different chromosomes together and creates a cancer-causing fusion gene called BCR-ABL. We have recently identified a number of genes that potentially act to suppress the development of BCR-ABL+ leukemias. The experiments proposed in this application will confirm the role(s) of these genes in suppressing BCR-ABL+ leukemias, identify the cellular pathways by which they act, and determine if they affect a patient's responsiveness to drugs used to treat BCR-ABL+ leukemias. Thus, the results of these experiments will improve our understanding of how BCR-ABL+ leukemias develop and can be effectively treated.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA163926-01A1
Application #
8578767
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Mufson, R Allan
Project Start
2013-09-11
Project End
2018-06-30
Budget Start
2013-09-11
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$345,488
Indirect Cost
$137,988
Name
University of Massachusetts Medical School Worcester
Department
Genetics
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655