Myelodysplastic syndromes (MDS) are heterogeneous disorders in which the hematopoietic stem cells (HSCs) are defective. MDS progresses to secondary acute myeloid leukemia (sAML) in about one third of patients, as additional genetic abnormalities are acquired. Epigenetic regulator MLL and transcription factor RUNX1 regulate normal hematopoiesis. We have shown that they form a complex to regulate downstream target genes. Mutations of MLL1 (in-frame partial-tandem-duplication, MLL-PTD, or MLL translocations) or RUNX1 are found in about 20-28% of MDS, particularly in high-risk MDS. sAML frequently contains both MLL-PTD and RUNX1 mutations (mRUNX1), arguing for cooperative leukemogenic synergy between these two molecular lesions. However, little is known about the molecular mechanisms underlying MDS/sAML-associated clonal evolution, ineffective hematopoiesis, and leukemic transformation. The goals of this project are to build robust and faithful mouse MDS models and to identify key targets that are critical for clonal evolution and pathogenesis of MDS/sAML. Recently, we built novel MDS mouse models by combination of MLL-PTD and Runx1 deletion or expression RUNX1 mutations in MLL-PTD background. According to our novel MDS mouse models, we identified hyperactivation of HIF-1alpha. HIF-1alpha is an essential transcription factor for hypoxic response, glycolytic energy production, HSC self-renewal, angiogenesis, systemic inflammation, immune response, fibrosis, and iron homeostasis. Thus, we hypothesize that MLL-PTD and RUNX1 mutants cooperatively activate HIF-1alpha, which contributes to the initiation, maintenance, and pathogenesis of MDS. Targeting HIF-1alpha will provide therapeutic benefit for many MDS patients. Indeed, blood specific transgenic mice expressing HIF-1alpha recapitulate the MDS phenotypes. Here we propose to determine, 1) the mechanism of HIF-1alpha up-regulation by MLL-PTD and MDS-patient-derived RUNX1 mutants; 2) the essential role of HIF-1alpha in murine and human MDS/sAML. Our study will not only provide stringent mechanistic tests of our hypotheses, but also lead to a better understanding of pathogenesis of MDS and to potential new therapeutic targets in MDS.

Public Health Relevance

We propose a novel concept of interplay between genetic/epigenetic regulators (RUNX1 and MLL1) and HIF-1alpha, a key regulator for hypoxic response, glycolytic energy production, HSC self-renewal, angiogenesis, systemic inflammation, immune response, fibrosis, and iron homeostasis. We hypothesize that MLL-PTD and RUNX1 mutants cooperatively aberrant activate HIF-1alpha which contributes to the initiation, maintenance, and pathogenesis of MDS. Indeed, blood specific HIF-1alpha transgenic mice recapitulate the MDS phenotypes as Mll- PTD/mRUNX1 models. We propose to determine, 1) the mechanism of HIF-1alpha up-regulation by MLL-PTD and MDS-patient-derived RUNX1 mutants; 2) the essential role of HIF-1alpha in murine and human MDS/sAML. Our study will not only provide stringent mechanistic tests of our hypotheses, but also lead to a better understanding of pathogenesis of MDS and to potential new therapeutic targets in MDS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK105014-05
Application #
9648137
Study Section
Molecular and Cellular Hematology Study Section (MCH)
Program Officer
Roy, Cindy
Project Start
2015-03-01
Project End
2020-02-29
Budget Start
2019-03-01
Budget End
2020-02-29
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Hayashi, Yoshihiro; Zhang, Yue; Yokota, Asumi et al. (2018) Pathobiological Pseudohypoxia as a Putative Mechanism Underlying Myelodysplastic Syndromes. Cancer Discov 8:1438-1457
Wang, Jieyu; Hayashi, Yoshihiro; Yokota, Asumi et al. (2018) Expansion of EPOR-negative macrophages besides erythroblasts by elevated EPOR signaling in erythrocytosis mouse models. Haematologica 103:40-50
Dong, Lei; Yu, Wen-Mei; Zheng, Hong et al. (2016) Leukaemogenic effects of Ptpn11 activating mutations in the stem cell microenvironment. Nature 539:304-308