MEK/ERK is a major signaling pathway downstream of Ras. Recently, we characterized conditional mouse models of human myeloproliferative diseases (MPDs) that express one or two copies of oncogenic Nras in the hematopoietic compartment (Nras G12D/+ and Nras G12D/G12D), respectively. In both MPD models, the MEK/ERK pathway is hyperactivated in hematopoietic stem/progenitor cells (HSPCs) upon cytokine stimulation. Moreover, genetically altered HSCs are required to initiate and maintain MPD phenotypes and thus serve as MPD initiating cells. Interestingly, unlike in HSPCs and other progenitors, we found that Nras G12D signaling constitutively hyperactivates ERK1/2 in HSCs in a dose-dependent manner. This aberrant signaling is associated with increased self-renewal capability of Nras G12D/+ HSCs but reduced self-renewal and exhaustion of Nras G12D/G12D HSCs. Consistently, microarray analysis identifies the MEK/ERK pathway as the most strongly affected functional gene ontology category in both groups of HSCs. Collectively, these studies raise the possibility that hyperactivation of the MEK/ERK pathway regulates the self-renewal and differentiation of HSCs in a dose-dependent manner and is a critical step leading to MPD. In support of this hypothesis, AZD6244, a MEK inhibitor, rescues exhaustion of Nras G12D/G12D HSCs, effectively controls MPD phenotypes, and significantly prolongs the survival of diseased mice. To further test our hypothesis in vivo, we have generated a novel conditional MEK1 knockin allele carrying point mutations that mimic phosphorylation at serine 218 and serine 222 (LSL MEK1 S218;222E). MEK1 S218;222E is a constitutively active form of MEK1. As a part of our long-term goal to elucidate novel signaling mechanisms that control hematopoiesis, the specific aims of this proposal are to: 1) determine whether hyperactivation of the MEK/ERK pathway is necessary and sufficient for Nras G12D-mediated MPD phenotypes;2) determine whether Nras G12D signaling regulates HSC self-renewal and differentiation through a dose-dependent activation of the MEK/ERK pathway;3) determine whether inhibition of MEK1/2 and Jak2 blocks Nras G12D/G12D-mediated MPD and its transformation to a blast crisis. Together, the experiments proposed in these two specific aims will provide insights into the central role of MEK/ERK signaling in hematopoiesis. These insights will not only bring us closer to understanding the role of genetically altered HSCs in tumorigenesis, but also improve fundamental understanding of developmental and myeloproliferative diseases caused by dysfunctional Ras/Raf/MEK signaling.

Public Health Relevance

The Ras/Raf/MEK/ERK pathway plays a critical role in maintaining an appropriate balance between proliferation and differentiation in the hematopoietic compartment. Gain-of-function mutations causing dysfunctional MEK/ERK signaling are common in several human developmental diseases and human cancers. Our research employs powerful genetically engineered mouse models and highly specific inhibitors of relevant cytokine signaling pathways to study the role of aberrant Ras/Raf/MEK/ERK signaling in regulating hematopoiesis. The proposed research is important and valuable because it has strong potential to help elucidate the critical mechanisms and pathways leading to human developmental and myeloproliferative diseases. The knowledge gained from these studies could lead to novel therapeutic regimens for treating human patients with these diseases in the clinic.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Molecular and Cellular Hematology (MCH)
Program Officer
Thomas, John
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Wisconsin Madison
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
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
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
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

Showing the most recent 10 out of 20 publications