The overall goal of this proposal is to understand the role of CSF2 and its specific receptor CSF2R? in the development of t(8;21) leukemia. The 8 and 21 chromosome translocation, t(8;21)(q22;q22), is responsible for the development of 40% of FAB M2 type of acute myeloid leukemia (AML) and is reported in 8-15% of cases of AML, depending on geographic locations and ethnic groups. Age is the most correlated factor for AML. Most AML patients are over 60 years old at the initial diagnosis. However, t(8;21) AML patients are relatively young and most respond to initial chemotherapy well. Therefore, t(8;21) AML is generally considered with favorable prognosis. However, the cumulative incidence of relapse in 5 years is 47%, and the median overall survival time is only 5 years among de novo t(8;21) AML patients. Furthermore, therapy-related t(8;21) AML does not have a favorable outcome. Therefore, it is important to identify new approaches to eliminate t(8;21) leukemia stem cells during the initial induction treatment and to block the survival and proliferation of chemo-resistant leukemia cells. The fusion of ETO gene on chromosome 8 and AML1 gene on chromosome 21 in t(8;21) leads to the expression of the abnormal AML1-ETO protein. Using several transgenic mouse models and available human patient data, we discovered that colony stimulating factor 2 (CSF2) negatively regulates AML1-ETO induced self-renewal of hematopoietic stem/progenitor cells and AML development. Furthermore, expression of the CSF2-specific receptor subunit, CSF2R?, in t(8;21) AML cells reduces cell proliferation and survival. In this funding application, we will test the hypotheses that selected CSF2 downstream pathways play critical roles in suppression of t(8;21) leukemia and that CSF2R? may have functions independent of CSF2 signaling in inhibition of t(8;21) leukemia. We propose to perform the following studies to test the hypotheses:
in specific aim 1, we will characterize the molecular pathways of CSF2 signaling that mediate inhibition of AML1-ETO induced leukemia;
in specific aim 2, we will analyze the effect of CSF2RA expression on t(8;21) leukemogenesis. The proposed studies are based on our accumulated knowledge and recent novel findings involving CSF2 signaling and CSF2R? in AML1-ETO induced leukemia. Collectively, our proposal will address important unanswered questions in hematopoiesis and leukemogenesis, which aim to provide valuable insight into the treatment of t(8;21) leukemia.

Public Health Relevance

Acute myeloid leukemia is a major form of blood cancer with very few targeted therapies. Aside from traditional non-specific chemotherapy with high toxicity to patients, there exist few alternative treatments and the standard of care remains insufficient. The aim of this application is to study cytokine CSF2 and its specific receptor in leukemia to provide molecular insights into acute myeloid leukemia to better develop novel and effective treatments.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA192924-05
Application #
9621368
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Duglas Tabor, Yvonne
Project Start
2015-02-13
Project End
2020-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California, San Diego
Department
Pathology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Weng, S; Matsuura, S; Mowery, C T et al. (2017) Restoration of MYC-repressed targets mediates the negative effects of GM-CSF on RUNX1-ETO leukemogenicity. Leukemia 31:159-169
Weng, Stephanie; Stoner, Samuel A; Zhang, Dong-Er (2016) Sex chromosome loss and the pseudoautosomal region genes in hematological malignancies. Oncotarget 7:72356-72372