Chronic myelomonocytic leukemia (CMML) is a devastating cancer for which there is currently no effective therapy. Approximately 20% of CMML cases evolve to acute myelogenous leukemia (AML) soon after their initial diagnosis. Oncogenic NRAS mutations, which are among the most frequently identified genetic mutations in myeloid diseases, are identified in 17-60% of CMML cases, including cases that transform to AML. However, it remains elusive how oncogenic, endogenously arising NRAS mutations leads to CMML and its transformation to AML. Recently, we established a mouse bone marrow transplantation model harboring an oncogenic G12D mutation in the endogenous Nras locus in which ~95% of recipient mice develop a myeloproliferative (MP) disease remarkably resembling the MP variant of human CMML. Our preliminary results suggest that endogenous oncogenic Nras signaling promotes HSC proliferation and mobility rather than apoptosis and senescence. We propose that genetically altered HSCs initiate and maintain CMML in this model. In addition, similar to what occurs in patients with CMML, aberrant GM-CSF (granulocyte-macrophage colony stimulating factor) signaling is a signature of our model, primarily regulating expansion of granulocytic/monocytic precursors. We hypothesize that this aberrant signaling drives inappropriate cell growth and survival during disease initiation and progression, and thus could constitute a valuable therapeutic target. Because CMML occurs after a prolonged latency accompanied by multiple additional genetic lesions in our model, we further hypothesize that, as for human CMML, oncogenic NRAS cooperates with mutations in other genes to either induce CMML or lead to CMML transformation to AML. As a part of our long-term goal to understand the molecular and cellular mechanisms in tumor initiation, progression, and malignant transformation, in this application we propose: 1) To determine the effects of endogenous oncogenic Nras signaling on the properties of HSCs and examine whether HSCs expressing oncogenic Nras initiate and maintain CMML;2) To determine whether aberrant GM-CSF signaling is essential to establish and/or maintain oncogenic Nras-initiated CMML-like phenotypes;3) To identify novel pathogenic origins involved in CMML and/or its transformation to AML using CMML patient samples and to validate cooperating mutations of oncogenic NRAS in our murine model of CMML. Successful accomplishment of the proposed studies will not only provide insights into the pathogenesis, progression, and transformation of CMML, but may also lead to novel insights into HSC regulation, aberrant cytokine signaling, and cooperating mutations in oncogenic NRAS- associated myeloid diseases in general.

Public Health Relevance

Chronic myelomonocytic leukemia (CMML) is a devastating disease that primarily affects the elderly. Although oncogenic NRAS mutations are frequently identified in CMML patients, its role remains unknown in initiation, progression, and malignant transformation of CMML. In this application, we propose to address this question using CMML patient samples and our new murine model of CMML. Furthermore, because oncogenic NRAS mutations are among the most frequently identified genetic mutations in myeloid diseases, successful completion of the proposed studies on HSC regulation, aberrant cytokine signaling, and validation of cooperating mutations of oncogenic NRAS have broad impact on understanding the role of NRAS mutations in hematological malignancies, including but not limiting to CMML.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01CA152108-04
Application #
8708774
Study Section
Molecular and Cellular Hematology (MCH)
Program Officer
Mufson, R Allan
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Madison
State
WI
Country
United States
Zip Code
53715
Kong, G; Chang, Y-I; You, X et al. (2016) The ability of endogenous Nras oncogenes to initiate leukemia is codon-dependent. Leukemia 30:1935-8
Kong, G; Chang, Y-I; Damnernsawad, A et al. (2016) Loss of wild-type Kras promotes activation of all Ras isoforms in oncogenic Kras-induced leukemogenesis. Leukemia 30:1542-51
Damnernsawad, Alisa; Kong, Guangyao; Wen, Zhi et al. (2016) Kras is Required for Adult Hematopoiesis. Stem Cells 34:1859-71
Chen, Yuhong; Zheng, Yongwei; You, Xiaona et al. (2016) Kras Is Critical for B Cell Lymphopoiesis. J Immunol 196:1678-85
Zhang, Jingfang; Kong, Guangyao; Rajagopalan, Adhithi et al. (2016) p53-/- synergizes with enhanced NrasG12D signaling to transform megakaryocyte-erythroid progenitors in acute myeloid leukemia. Blood :
Johnson, Kirby D; Kong, Guangyao; Gao, Xin et al. (2015) Cis-regulatory mechanisms governing stem and progenitor cell transitions. Sci Adv 1:e1500503
Chang, Y-I; You, X; Kong, G et al. (2015) Loss of Dnmt3a and endogenous Kras(G12D/+) cooperate to regulate hematopoietic stem and progenitor cell functions in leukemogenesis. Leukemia 29:1847-56
Liu, Zhenjie; Morgan, Stephanie; Ren, Jun et al. (2015) Thrombospondin-1 (TSP1) contributes to the development of vascular inflammation by regulating monocytic cell motility in mouse models of abdominal aortic aneurysm. Circ Res 117:129-41
Zhang, Jingfang; Ranheim, Erik A; Du, Juan et al. (2015) Deficiency of β Common Receptor Moderately Attenuates the Progression of Myeloproliferative Neoplasm in NrasG12D/+ Mice. J Biol Chem 290:19093-103
Wang, Tongjie; Li, Chen; Xia, Chengxiang et al. (2015) Oncogenic NRAS hyper-activates multiple pathways in human cord blood stem/progenitor cells and promotes myelomonocytic proliferation in vivo. Am J Transl Res 7:1963-73

Showing the most recent 10 out of 23 publications