The long-term goal of the Qian laboratory is to understand the mechanisms that underlie the development of blood cancer with a focus on studying the genetic pathways that control the proliferation, survival and self-renewal of normal or leukemic hematopoietic stem cells, and to identify novel therapeutic strategies for treatment of myeloid malignant diseases. Currently our lab research interests include 1) understanding the molecular regulation of normal hematopoietic stem cells (HSCs) and their leukemic transformation, 2) determining the role and mechanisms of the Wnt/β-catenin signaling in the development and maintenance of myeloid neoplasms, 3) understanding transcriptional, epigenetic and epitranscriptome regulation of normal hematopoiesis and leukemogenesis, 4) studying post-translational modifications of RNA m6A methylation regulators in cancer, and 5) developing novel targeted therapies for myeloid malignant diseases and solid tumors including lung and head-neck cancers.
FOXM1 regulates leukemia stem cell quiescence and survival in MLL-rearranged AML
FOXM1, a known transcription factor, promotes cell proliferation in a variety of cancer cells. Here we show that Foxm1 is required for survival, quiescence and self-renewal of MLL-AF9 (MA9)-transformed leukemia stem cells (LSCs) in vivo. Mechanistically, Foxm1 upregulation activates the Wnt/β-catenin signaling pathways by directly binding to β-catenin and stabilizing β-catenin protein through inhibiting its degradation, thereby preserving LSC quiescence, and promoting LSC self-renewal in MLL-rearranged AML. More importantly, inhibition of FOXM1 markedly suppresses leukemogenic potential and induces apoptosis of primary LSCs from MLL-rearranged AML patients in vitro and in vivo in xenograft mice. Thus, our study shows a critical role and mechanisms of Foxm1 in MA9-LSCs, and indicates that FOXM1 is a potential therapeutic target for selectively eliminating LSCs in MLL-rearranged AML.
Sheng, Y., Yu, C., Liu, Y. et al. FOXM1 regulates leukemia stem cell quiescence and survival in MLL-rearranged AML. Nat Commun 11, 928 (2020). https://doi.org/10.1038/s41467-020-14590-9
Role of c-Myc haploinsufficiency in the maintenance of HSCs in mice
This study was conducted to determine the dosage effect of c-Myc on hematopoiesis and its distinct role in mediating the Wnt/β-catenin pathway in hematopoietic stem cell (HSC) and bone marrow niche cells. c-Myc haploinsufficiency led to ineffective hematopoiesis by inhibiting HSC self-renewal and quiescence and by promoting apoptosis. We have identified Nr4a1, Nr4a2, and Jmjd3, which are critical for the maintenance of HSC functions, as previously unrecognized downstream targets of c-Myc in HSCs. c-Myc directly binds to the promoter regions of Nr4a1, Nr4a2, and Jmjd3 and regulates their expression. Our results revealed that Nr4a1 and Nr4a2 mediates the function of c-Myc in regulating HSC quiescence, whereas all 3 genes contribute to the function of c-Myc in the maintenance of HSC survival. Adenomatous polyposis coli (Apc) is a negative regulator of the Wnt/β-catenin pathway. We have provided the first evidence that Apc haploinsufficiency induces a blockage of erythroid lineage differentiation through promoting secretion of IL6 in bone marrow endothelial cells. We found that c-Myc haploinsufficiency failed to rescue defective function of Apc-deficient HSCs in vivo but it was sufficient to prevent the development of severe anemia in Apc–heterozygous mice and to significantly prolong the survival of those mice. Furthermore, we showed that c-Myc–mediated Apc loss induced IL6 secretion in endothelial cells, and c-Myc haploinsufficiency reversed the negative effect of Apc-deficient endothelial cells on erythroid cell differentiation. Our studies indicate that c-Myc has a context-dependent role in mediating the function of Apc in hematopoiesis.
Yue Sheng, Rui Ma, Chunjie Yu, Qiong Wu, Steven Zhang, Kimberly Paulsen, Jiwang Zhang, Hongyu Ni, Yong Huang, Yi Zheng, Zhijian Qian; Role of c-Myc haploinsufficiency in the maintenance of HSCs in mice. Blood 2021; 137 (5): 610–623. doi: https://doi.org/10.1182/blood.2019004688
Molecular regulation of normal and leukemic hematopoietic stem cells
Sheng Y, Yu C, Liu Y, Hu C, Ma R, Lu X, Ji P, Chen J, Mizukawa B, Huang Y, Licht JD and Qian Z*. FOXM1 Regulates Leukemia Stem Cell Quiescence and Survival in MLL-Rearranged AML. Nature Communication. (2020) 11:928
Sheng Y, Ma R, Yu C, Paulsen K, Zhang J, Ni H, Huang Y and Qian Z*. Context dependent role of c-Myc in mediating the Wnt/b-catenin signaling in hematopoiesis. Blood 2020, August 21
Hou Y, Li W, Sheng Y, Huang Y, Li L, Zhang Z, Peace D, Quigley JG, Wu W, Zhao YY, and Qian Z*. FoxM1 is essential for quiescence and maintenance of hematopoietic stem cell. Nat Immunol Published online 29 June 2015. doi:10.1038/ni.3204
Hou Y, Wang X, Li L, Fan R, Chen, J, Zhu, T, Li W, Jiang Y, Mittal N, Wu W, Peace D, Qian Z*. FHL2 regulates hematopoietic stem cell functions under stress conditions. Leukemia. 2015 Mar;29(3):615-24. doi: 10.1038/leu.2014.254. Epub 2014 Sep 2.PMID: 25179730
Li WS, Hou Y, Ming M, Yu L, Seba, A, Qian Z*. Apc regulates the function of hematopoietic stem cell through beta-catenin-dependent and independent mechanisms. Blood. 2013 Apr 1. [Epub ahead of print] PMID: 23547052
Qian, Z*, Chen L, Fernald A, Williams B and Le Beau MM. A critical role for Apc in hematopoietic stem cell survival. J Exp Med. 2008, 205:2163-75. PMID: 18725524 (*, corresponding author)
The role and mechanism of the Wnt/b-catenin signaling in the development and maintenance of myeloid neoplasms
Li L, Sheng Y, Li W, Hu C, Mittal N, Tohyama K, Seba A, Zhao YY, Ozer H, Zhu T, Qian Z*. β- Catenin is a candidate therapeutic target for myeloid neoplasms with del(5q). Cancer Research. 2017 Aug 1;77(15):4116-4126.
Y Sheng, W Ju, Y Huang, J Li, H Ozer, Qiao and Qian Z*. Activation of Wnt/β-catenin signaling blocks monocyte-macrophage differentiation through antagonizing PU.1-targeted gene transcription. Leukemia 2016 doi:10.1038/leu.2016.146.
Ming M, Wang S, Wu W, Senyuk V, Le Beau MM, Nucifora G, Qian Z*. Activation of Wnt/β-catenin signaling induces mitochondrial-mediated apoptosis in hematopoietic progenitor cells. J Biol Chem. 2012 May 15. [Epub ahead of print]. PMID: 22589536.
Wang JH, Fernald A, Le Beau MM, Qian Z*. Haploinsufficiency of Apc leads to ineffective hematopoiesis. Blood. 2010, 115 (17): 3481-8.
Transcriptional, epigenetic and epitranscriptome regulation of leukemogenesis
Shen C, Sheng Y, Zhu A, Robinson S, Jiang X, Dong L, Chen H, Su R, Yin Z, Li W, Deng X, Chen Y, Hu Y, Wng H, Hunag H, Prince E, Cogle C, Sun M, Zhang B, Chen C, Marcucci G, He C*, Qian Z* and Chen J*.m6A demethylase ALKBH5 selectively promotes tumorigenesis and cancer stem cell self-renewal in acute myeloid leukemia. Cell Stem Cell 2020, May 12, 2020DOI:*Co-corresponding author
Huang Y, Su R, Sheng Y, Dong L, Dong Z, Xu H, Ni T, Zhang Z, Zhang T, Li C, Han L, Zhu Z, Fulin Lian F, Wei J, Deng Q,Wang Y, Wunderlich M, GaoZ, Pan G, Zhong D, Zhou H, Zhang N, Gan J, Jiang H, Mulloy JC, Qian Z*, Chen J*, Yang CG*. Small-molecule targeting of oncogenic FTO demethylase in acute myeloid leukemia. Cancer Cell 2019 Apr 15;35(4):677-691.e10. doi: 10.1016/j.ccell.2019.03.006. PMID: 30991027 (*, Co-corresponding author)
SenyukV, Zhang YY, Liu Y, Ming M, PremanandK, Zhou L, Chen P, Chen J, RowleyJ, Nucifora G, and Qian Z*. A critical role of miR-9 in myelopoiesis and EVI1-induced leukemogenesis. Proc Natl Acad Sci U S A. 2013 Mar 18. [Epub ahead of print] PMID: 23509296
Qian Z*, Mao L, Fernald A, Yu H, Luo R, Anastasi J, Delwel R and Le Beau MM. The FHL2 LIM- Domain Protein Is Implicated in Hematopoiesis and Leukemogenesis. Leukemia. 2009, 23(9):1650-7. PMID: 19369964 (*, corresponding author)