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, contributing to the poor prognosis of CMML patients (median survival: ~20 months). While recent sequencing efforts identified numerous genetic mutations in CMML, translating these genomic data into physiological mechanisms and therapeutics remains very challenging. This challenge arises from the incomplete genetic/epigenetic landscape of CMML and limitations to mechanistically define genetic interactions of various mutations. Studies during the prior funding period leveraged our innovative CMML mouse model induced by endogenous oncogenic Nras (NrasG12D/+). Based on our recent results from this and its derived models as well as results from whole exome sequencing of patient samples, we hypothesize that the genetic interaction between oncogenic Ras signaling and mutations in epigenetic regulators forms a positive feedback loop to further strengthen the signaling network and select for additional mutations in epigenetic regulators during CMML progression and transformation to AML. Therefore, effective targeting of oncogenic Ras signaling or simultaneous targeting Ras signaling and aberrant epigenetic landscape could be promising therapeutic strategies against CMML progression, transformation to AML, and/or AML progression. 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 how NrasG12D cooperates with mutations in epigenetic regulators to promote CMML development; 2) To determine whether combined therapies effectively control CMML progression, transformation to AML, and/or AML progression in vivo. Successful accomplishment of the proposed studies will not only provide insights into the initiation, progression and transformation of CMML, but may also lead to novel insights into myeloid diseases with RAS pathway mutations and mutations in epigenetic regulators in general.

Public Health Relevance

Chronic myelomonocytic leukemia (CMML) is a devastating disease that primarily affects the elderly. Oncogenic NRAS mutations are frequently identified in CMML patients. In the prior funded period, we focused on its role in initiation and progression of CMML. In this application, we propose to investigate how the genetic interaction between oncogenic Nras signaling and mutations in epigenetic regulators promotes CMML progression and transformation to AML. Furthermore, we will determine whether effective targeting of oncogenic Ras signaling or simultaneous targeting Ras signaling and aberrant epigenetic landscape could be promising therapeutic strategies against CMML progression, transformation to AML, and/or AML progression in vivo. Because oncogenic NRAS mutations are associated with mutations in epigenetic regulators in multiple myeloid diseases, successful completion of the proposed studies has broad impact on understanding their genetic interaction in hematological malignancies, including but not limiting to CMML.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA152108-07
Application #
9443588
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Duglas Tabor, Yvonne
Project Start
2011-09-02
Project End
2022-02-28
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
7
Fiscal Year
2018
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
Peng, Yajing; Shapiro, Samantha L; Banduseela, Varuna C et al. (2018) Increased transport of acetyl-CoA into the endoplasmic reticulum causes a progeria-like phenotype. Aging Cell 17:e12820
Lu, Zhanping; Hong, Courtney C; Kong, Guangyao et al. (2018) Polycomb Group Protein YY1 Is an Essential Regulator of Hematopoietic Stem Cell Quiescence. Cell Rep 22:1545-1559
You, Xiaona; Kong, Guangyao; Ranheim, Erik A et al. (2018) Unique dependence on Sos1 in Kras G12D -induced leukemogenesis. Blood 132:2575-2579
Pang, Yanbin; Deng, Chengxin; Geng, Suxia et al. (2017) Premature exhaustion of mesenchymal stromal cells from myelodysplastic syndrome patients. Am J Transl Res 9:3462-3468
Chang, Yuan-I; Kong, Guangyao; Ranheim, Erik A et al. (2017) Dnmt3a haploinsufficiency cooperates with oncogenicKrasto promote an early-onset T-cell acute lymphoblastic leukemia. Am J Transl Res 9:1326-1334
Zhang, Jingfang; Kong, Guangyao; Rajagopalan, Adhithi et al. (2017) p53-/- synergizes with enhanced NrasG12D signaling to transform megakaryocyte-erythroid progenitors in acute myeloid leukemia. Blood 129:358-370
Chen, Yuhong; Zheng, Yongwei; You, Xiaona et al. (2016) Kras Is Critical for B Cell Lymphopoiesis. J Immunol 196:1678-85
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
Damnernsawad, Alisa; Kong, Guangyao; Wen, Zhi et al. (2016) Kras is Required for Adult Hematopoiesis. Stem Cells 34:1859-71
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

Showing the most recent 10 out of 28 publications