My laboratory primarily focuses on both genetic and epigenetic mechanisms in hematopoietic stem and progenitor cells, with each project guided by methods intended to elucidate basic principles as well as practical solutions. Leukemia and other hematological disorders are the main diseases against which advancements in the laboratory are targeted. Through broadly collaborative approaches, I am also committed to training hematologists and stem cell biologists and to building strong and competitive hematology and stem cell research programs that will ultimately benefit the patients.
Teaching Activities:
- Graduate student courses:
Experimental Hematology; Cell therapy; Stem cell biology
Now I am supervising 9 Ph.D. students, 5 master students, and 2 postdocs.
Representative Publications
Zhu X, He F, Zeng H, Ling S, Chen A, Wang Y, Yan X, Wei W, Pang Y, Cheng H, Hua C, Zhang Y, Yang X, Lu X, Cao L, Hao L, Dong L, Zou W, Wu J, Li X, Zheng S, Yan J, Zhou J, Zhang L, Mi S, Wang X, Zhang L, Zou Y, Chen Y, Geng Z, Wang J, Zhou J, Liu X, Wang J, Yuan W, Huang G*, Cheng T*, Wang QF*(co-*co-corresponding authors). Identification of functional cooperative mutations of SETD2 in human acute leukemia. Nature Genetics. 2014 Mar;46(3):287-93.
Yao Y, Lu Y, Chen WC, Jiang Y, Cheng T, Ma Y, Lu L, Dai W. Cobalt and Nickel Stabilize Stem Cell Transcription Factor OCT4 through Modulating Its Sumoylation and Ubiquitination. PLoS One. 2014 Jan 31;9(1):e86620.
Lan Y, He W, Li Z, Wang Y, Wang J, Gao J, Wang W, Cheng T, Liu B, Yang X. Endothelial Smad4 restrains the transition to hematopoietic progenitors via suppression of ERK activation. Blood. 2014 Feb 19.
Ping XL, Sun BF, Wang L, Xiao W, Yang X, Wang WJ, Adhikari S, Shi Y, Lv Y, Chen YS, Zhao X, Li A, Yang Y, Dahal U, Lou XM, Liu X, Huang J, Yuan WP, Zhu XF, Cheng T, Zhao YL, Wang X, Rendtlew Danielsen JM, Liu F, Yang YG. Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Research. 2014 Feb;24(2):177-89. doi: 10.1038/cr.2014.3. Epub 2014 Jan 10.
Leibowitz BJ, Wei L, Zhang L, Ping X, Epperly M, Greenberger J, Cheng T, Yu J. Ionizing irradiation induces acute haematopoietic syndrome and gastrointestinal syndrome independently in mice. Nature Communications. 2014 Mar 18;5:3494.
Li C, Bai J, Hao X, Zhang S, Hu Y, Zhang X, Yuan W, Hu L, Cheng T, Zetterberg A, Lee MH, Zhang J.Multi-gene fluorescence in situ hybridization to detect cell cycle gene copy number aberrations in young breast cancer patients. Cell Cycle. 2014 Apr 15;13(8):1299-305.
Chang L, Yuan W, Zeng H, Zhou Q, Wei W, Zhou J, Li M, Wang X, Xu M, Yang F, Yang Y, Cheng T*, Zhu X*(co-*co-corresponding authors). Whole exome sequencing reveals concomitant mutations of multiple FA genes in individual Fanconi anemia patients. BMC Medical Genomics. 2014 May 15;7:24. doi: 10.1186/1755-8794-7-24.
Lin Y, Hu X, Cheng H, Pang Y, Wang L, Zou L, Xu S, Zhuang X, Jiang C, Yuan W, Cheng T*, Wang J*(co-*co-corresponding authors). Graft-Versus-Host Disease Causes Broad Suppression of Hematopoietic Primitive Cells and Blocks Megakaryocyte Differentiation in a Murine Model. Biology of Blood and Marrow Transplantation. 2014 May 15. pii: S1083-8791(14)00294-8. doi: 10.1016/j.bbmt.2014.05.009.
An G, Wang H, Qin X, Shi L, Xu Y, Deng S, Sui W, Zhu G, Yao H, Yi S, Qin Y, Li F, Hao M, Ru K, Qi J, Cheng T, Wang J, Chang H, Qiu L. Polyclonal serum IgM level identifies a subgroup of multiple myeloma patients with low-risk clinicobiological features and superior survival. Leukemia Research. 2014 Jun;38(6):666-72. doi: 10.1016/j.leukres.2014.02.009.
Song B, Zhang Q, Zhang Z, Wan Y, Jia Q, Wang X, Zhu X, Leung AY, Cheng T, Fang X, Yuan W, Jia H. Systematic transcriptome analysis of the zebrafish model of diamond-blackfan anemia induced by RPS24 deficiency. BMC Genomics. 2014 Sep 4;15(1):759.
Zhang Y, Hu T, Hua C, Gu J, Zhang L, Hao S, Liang H, Wang X, Wang W, Xu J, Liu H, Liu B, Cheng T*, Yuan W*(co-*co-corresponding authors). Rictor is required for early B cell development in bone marrow. PLoS One. 2014 Aug 1;9(8):e103970. doi: 10.1371/journal.pone.0103970.
Hua C, Guo H, Bu J, Zhou M, Cheng H, He F, Wang J, Wang X, Zhang Y, Wang Q, Zhou J, Cheng T, Xu M, Yuan W. Rictor/mTORC2 regulates the development of notch1 induced murine T-ALL via FoxO3a. Experimental Hematology. 2014 Sep 5.
Ma S, Shi Y, Pang Y, Dong F, Cheng H, Hao S, Xu J, Zhu X, Yuan W, Cheng T*, Zheng G* (co-*co-corresponding authors). Notch1-induced T cell leukemia can be potentiated by microenvironmental cues in the spleen. Journal of Hematology & Oncology. 2014 Nov 4;7(1):71.
Hu L, Cheng H, Gao Y, Shi M, Liu Y, Hu Z, Xu J, Qiu L, Yuan W, Leung AY, Yang YG, Cheng T. The antioxidant N-acetyl-L-cysteine increases engraftment of human hematopoietic stem cells in immune-deficient mice. Blood. 2014 Nov 13;124(20):e45-8.
Zhang Y, Peng L, Hu T, Wan Y, Ren Y, Zhang J, Wang X, Zhou Y, Yuan W, Wang Q, Cheng T, Zhu X. La-related protein 4B maintains murine MLL-AF9 leukemia stem cell self-renewal by regulating cell cycle progression. Experimental Hematology. 2014 Dec 19. pii: S0301-472X(14)00815-7. doi: 10.1016/j.exphem.2014.12.003. [Epub ahead of print]
Kwak HJ, Liu P, Bajrami B, Xu Y, Park SY, Nombela-Arrieta C, Mondal S, Sun Y, Zhu H, Chai L, Silberstein LE, Cheng T, Luo HR. Myeloid Cell-Derived Reactive Oxygen Species Externally Regulate the Proliferation of Myeloid Progenitors in Emergency Granulopoiesis. Immunity. 2015 Jan 7. pii: S1074-7613(14)00484-1. doi: 10.1016/j.immuni.2014.12.017. [Epub ahead of print]
Gao Y, Yang P, Shen H, Yu H, Song X, Zhang L, Zhang P, Cheng H, Xie Z, Hao S, Dong F, Ma S, Ji Q, Bartlow P, Ding Y, Wang L, Liu H, Li Y, Cheng H, Miao W, Yuan W, Yuan Y, Cheng T*, Xie XQ*. Small-molecule inhibitors targeting INK4 protein p18(INK4C) enhance ex vivo expansion of haematopoietic stem cells. Nature Communication 2015 Feb 18;6:6328. doi: 10.1038/ncomms7328.
Li J, Su W, Zhang S, Hu Y, Liu J, Zhang X, Bai J, Yuan W, Hu L, Cheng T, Zetterberg A, Lei Z, Zhang J. EGFR and AKT1 Gene Copy Numbers by Multi-Gene Fluorescence in Situ Hybridization Impact on Prognosis in Breast Cancer. Cancer Science. 2015 Feb 20. doi: 10.1111/cas.12637.
An G, Acharya C, Deng S, Yi S, Xu Y, Qin X, Sui W, Li Z, Shi L, Zang M, Feng X, Hao M, Zou D, Zhao Y, Qi J, Cheng T, Ru K, Wang J, Tai YT, Qiu L. Cytogenetic and clinical marks for defining high-risk myeloma in the context of bortezomib treatment. Exp Hematol. 2015 Mar;43(3):168-176.e2.
Hu T, Li C, Zhang Y, Wang L, Peng L, Cheng H, Wang W, Chu Y, Xu M, Cheng T, Yuan W. Phosphoinositide-dependent kinase 1 regulates leukemia stem cell maintenance in MLL-AF9-induced murine acute myeloid leukemia. Biochemical and Biophysical Research Communications 2015 Mar 11. pii: S0006-291X(15)00432-5. doi: 10.1016/j.bbrc.2015.03.007.
Chou BK, Gu H, Gao Y, Dowey SN, Wang Y, Shi J, Li Y, Ye Z, Cheng T, Cheng L. A facile method to establish human induced pluripotent stem cells from adult blood cells under feeder-free and xeno-free culture conditions: a clinically compliant approach. Stem Cells Translational Medicine. 2015 Apr;4(4):320-32.
An G, Li Z, Tai YT, Acharya C, Li Q, Qin X, Yi S, Xu Y, Feng X, Li C, Zhao J, Shi L, Zang M, Deng S, Sui W, Hao M, Zou D, Zhao Y, Qi J, Cheng T, Ru K, Wang J, Anderson KC, Qiu L. The impact of clone size on the prognostic value of chromosome aberrations by fluorescence in situ hybridization in multiple myeloma. Clin Cancer Res. 2015 May 1;21(9):2148-56.
Shi X, He BL, Ma AC, Guo Y, Chi Y, Man CH, Zhang W, Zhang Y, Wen Z, Cheng T, Leung AY. Functions of idh1 and its mutation in the regulation of developmental hematopoiesis in zebrafish. Blood. 2015 Mar 16. pii: blood-2014-09-601187.
Li F, Xu Y, Deng P, Yang Y, Sui W, Jin F, Hao M, Li Z, Zang M, Zhou D, Gu Z, Ru K, Wang J, Cheng T, Qiu L. Heterogeneous chromosome 12p deletion is an independent adverse prognostic factor and resistant to bortezomib-based therapy in multiple myeloma. Oncotarget. 2015 Mar 20.
Chen Z, Yi W, Morita Y, Wang H, Cong Y, Liu JP, Xiao Z, Rudolph KL, Cheng T, Ju Z. Wip1 deficiency impairs haematopoietic stem cell function via p53 and mTORC1 pathways. Nature Communication. 2015 Apr 16;6:6808.
Xie YL, Bai H, Liu Y, Hoyle DL, Cheng T, Wang ZZ. Cooperative Effect of Erythropoietin and TGF-β Inhibition on Erythroid Development in Human Pluripotent Stem Cells. Journal of Cellular Biochemistry. 2015 May 26.
Jiang C, Hu X, Wang L, Cheng H, Lin Y, Pang Y, Yuan W, Cheng T, Wang J. Excessive proliferation and impaired function of primitive hematopoietic cells in bone marrow due to senescence post chemotherapy in a T cell acute lymphoblastic leukemia model. Journal of Translational Medicine 2015 Jul 17;13(1):234.
Cheng H, Hao S, Liu Y, Pang Y, Ma S, Dong F, Xu J, Zheng G, Li S, Yuan W, Cheng T*. Leukemic marrow infiltration reveals a novel role for Egr3 as a potent inhibitor of normal hematopoietic stem cell proliferation. Blood. 2015 Jul 17. pii: blood-2015-01-623645.
Lim M, Pang Y, Ma S, Hao S, Shi H, Zheng Y, Hua C, Gu X, Yang F, Yuan W, Cheng T*. Altered mesenchymal niche cells impede generation of normal hematopoietic progenitor cells in leukemic bone marrow. Leukemia. 2015 Aug 4. doi: 10.1038/leu.2015.210.
Fu R, Liu D, Cao Z, Zhu S, Li H, Su H, Zhang L, Xue F, Liu X, Zhang X, Cheng T, Yang R, Zhang L. Distinct molecular abnormalities underlie unique clinical features of essential thrombocythemia in children. Leukemia. 2015 Jun 29. doi: 10.1038/leu.2015.167.
Li S, Zou D, Li C, Meng H, Sui W, Feng S, Cheng T, Zhai Q, Qiu L. Targeting stem cell niche can protect hematopoietic stem cells from chemotherapy and G-CSF treatment. Stem Cell Research & Therapy. 2015 Sep 15;6(1):175. doi: 10.1186/s13287-015-0164-4.
Zhao Y, Zhou J, Liu D, Dong F, Cheng H, Wang W, Pang Y, Wang Y, Mu X, Ni Y, Li Z, Xu H, Hao S, Wang X, Ma S, Wang QF, Xiao G, Yuan W, Liu B*, Cheng T*. ATF4 plays a pivotal role in the development of functional hematopoietic stem cells in mouse fetal liver. Blood. 2015 Nov 19;126(21):2383-91.
Li F, Hu L, Xu Y, Li Z, Yi S, Gu Z, Li C, Hao M, Ru K, Zhan F, Zetterberg A, Yuan W, Cheng T, Qiu L. Identification of characteristic and prognostic values of chromosome 1p abnormality by multi-gene fluorescence in situ hybridization in multiple myeloma. Leukemia. 2015 Sep 16.
Bai H, Liu Y, Xie Y, Hoyle DL, Brodsky RA, Cheng L, Cheng T, Wang ZZ. Definitive Hematopoietic Multipotent Progenitor Cells Are Transiently Generated from Hemogenic Endothelial Cells in Human Pluripotent Stem Cells. Journal of Cellular Physiology. 2015 Sep 23. doi: 10.1002/jcp.25199.
Yi S, Zou D, Li C, Zhong S, Chen W, Li Z, Xiong W, Liu W, Liu E, Cui R, Ru K, Zhang P, Xu Y, An G, Lv R, Qi J, Wang J, Cheng T, Qiu L. High incidence of MYC and BCL2 abnormalities in mantle cell lymphoma, although only MYC abnormality predicts poor survival. Oncotarget. 2015 Oct 23. doi: 10.18632/oncotarget.5705.
Wang Y, Chen C, Dong F, Ma S, Xu J, Gong Y, Cheng H, Zhou Y, Cheng T*, Hao S*. (Co-Corresponding authors) NK cells play a significant role in immunosurveillance at the early stage of MLL-AF9 acute myeloid leukemia via CD226/CD155 interactions. SCIENCE CHINA Life Sciences. 2015 Nov 20.
Xie XQ, Yang P, Zhang Y, Zhang P, Wang L, Ding Y, Yang M, Tong Q, Cheng H, Ji Q, McGuire T, Yuan W, Cheng T*, Gao Y*. (Co-Corresponding authors) Discovery of novel INK4C small-molecule inhibitors to promote human and murine hematopoietic stem cell ex vivo expansion. Scientific Reports. 2015 Dec 18;5:18115.
Wan Y, Zhang Q, Zhang Z, Song B, Wang X, Zhang Y, Jia Q, Cheng T, Zhu X, Leung AY, Yuan W, Jia H, Fang X. Transcriptome analysis reveals a ribosome constituents disorder involved in the RPL5 downregulated zebrafish model of Diamond-Blackfan anemia. BMC Medical Genomics. 2016 Mar 9;9:13. doi: 10.1186/s12920-016-0174-9.
Wang Y, Gao A, Zhao H, Lu P, Cheng H, Dong F, Gong Y, Ma S, Zheng Y, Zhang H, Zhang Y, Xu J, Zhu X, Yuan W, Zhang X, Hao S, Cheng T. Leukemia cell infiltration causes defective erythropoiesis partially through MIP-1α/CCL3. Leukemia. 2016 Apr 25. doi: 10.1038/leu.2016.81.
Zheng Y, Zhang H, Wang Y, Li X, Lu P, Dong F, Pang Y, Ma S, Cheng H, Hao S, Tang F, Yuan W, Zhang X, Cheng T. Loss of Dnmt3b accelerates MLL-AF9 leukemia progression. Leukemia. 2016 May 2. doi: 10.1038/leu.2016.112.
Cheng H, Liu Y, Jia Q, Ma S, Yuan W, Jia H, Cheng T. Novel regulators in hematopoietic stem cells can be revealed by a functional approach under leukemic condition. Leukemia. 2016 May 2. doi: 10.1038/leu.2016.118.
Wen W, Zhang JP, Xu J, Su RJ, Neises A, Ji GZ, Yuan W, Cheng T*, Zhang XB*. (Co-Corresponding authors) Enhanced Generation of Integration-free iPSCs from Human Adult Peripheral Blood Mononuclear Cells with an Optimal Combination of Episomal Vectors. Stem Cell Reports. 2016 May 3. pii: S2213-6711(16)30030-3. doi: 10.1016/j.stemcr.2016.04.005.
Wang X, Li M, Gao Y, Gao J, Yang W, Liang H, Ji Q, Li Y, Liu H, Huang J, Cheng T, Yuan W. Rheb1-mTORC1 maintains macrophage differentiation and phagocytosis in mice. Exp Cell Res. 2016 May 6. pii: S0014-4827(16)30107-0. doi: 10.1016/j.yexcr.2016.04.017.
Zhou F, Li X, Wang W, Zhu P, Zhou J, He W, Ding M, Xiong F, Zheng X, Li Z, Ni Y, Mu X, Wen L, Cheng T, Lan Y, Yuan W, Tang F, Liu B. Tracing haematopoietic stem cell formation at single-cell resolution. Nature. 2016 May 18;533(7604):487-92. doi: 10.1038/nature17997.
Gao Y, Gao J, Li M, Zheng Y, Wang Y, Zhang H, Wang W, Chu Y, Wang X, Xu M, Cheng T, Ju Z, Yuan W. Rheb1 promotes tumor progression through mTORC1 in MLL-AF9-initiated murine acute myeloid leukemia. J Hematol Oncol. 2016 Apr 12;9:36. doi: 10.1186/s13045-016-0264-3.
Dong F, Hao S, Ma S, Cheng H, Wang Y, Zhou W, Yuan W, Ema H, Cheng T. A novel lymphoid progenitor cell population (LSKlow) is restricted by p18INK4c. Exp Hematol. 2016 Jun 8. pii: S0301-472X(16)30164-3. doi: 10.1016/j.exphem.2016.05.015.
Zhang JP, Li XL, Neises A, Chen W, Hu LP, Ji GZ, Yu JY, Xu J, Yuan WP, Cheng T*, Zhang XB*(co-corresponding authors). Different Effects of sgRNA Length on CRISPR-mediated Gene Knockout Efficiency. Sci Rep. 2016 Jun 24;6:28566. doi: 10.1038/srep28566.
Yi S, Li Z, Zou D, An G, Cui R, Zhong S, Li H, Xiong W, Li C, Chen W, Liu W, Lv R, Yu Z, Wang H, Xu Y, Zhou K, Ru K, Wang J, Cheng T, Qiu L. Intratumoral genetic heterogeneity and number of cytogenetic aberrations provide additional prognostic significance in chronic lymphocytic leukemia. Genet Med. 2016 Jul 28.
Zhang H, Cheng H, Wang Y, Zheng Y, Liu Y, Liu K, Xu J, Hao S, Yuan W, Zhao T, Cheng T. Reprogramming of Notch1-induced acute lymphoblastic leukemia cells into pluripotent stem cells in mice. Blood Cancer J. 2016 Jul 8;6(7):e444.
Research Interests
Acute leukemia characterized by chromosomal rearrangements requires additional molecular disruptions to develop into full-blown malignancy, yet the cooperative mechanisms remain elusive. Using whole-genome sequencing of a pair of monozygotic twins discordant for MLL (also called KMT2A) gene-rearranged leukemia, we identified a transforming MLL-NRIP3 fusion gene and biallelic mutations in SETD2 (encoding a histone H3K36 methyltransferase). Moreover, loss-of-function point mutations in SETD2 were recurrent (6.2%) in 241 patients with acute leukemia and were associated with multiple major chromosomal aberrations. We observed a global loss of H3K36 trimethylation (H3K36me3) in leukemic blasts with mutations in SETD2. In the presence of a genetic lesion, downregulation of SETD2 contributed to both initiation and progression during leukemia development by promoting the self-renewal potential of leukemia stem cells. Therefore, our study provides compelling evidence for SETD2 as a new tumor suppressor. Disruption of the SETD2-H3K36me3 pathway is a distinct epigenetic mechanism for leukemia development.
Mortality and morbidity associated with leukemia are largely due to frequently occurring cytopenias or the dysfunction of normal blood cells in patients. Our knowledge of how normal blood cells degenerate in response to leukemic cell infiltration has been quite limited. My talk is going to summarize recent findings and discusses both extrinsic and intrinsic mechanisms underlying the suppression of normal hematopoiesis in leukemia. Recent studies (including our own work) have shown that leukemic cells are able to remodel the bone marrow niche by secreting specific cytokines or dampening its hematopoietic-supporting functions. In turn, a suitable microenvironment for leukemic cell proliferation but not for normal hematopoietic cell growth is created. Intrinsically, the leukemic condition impairs the normalcy of hematopoietic stem and progenitor cells and alters their signaling networks; consequently, it exhausts hematopoietic progenitor cells and forces stem cells into a more quiescent state, which would allow a reversible suppression of hematopoietic regeneration. The deepened quiescence of hematopoietic stem cells in leukemic marrow was achieved in part via transcription factor Egr3. These findings provide new insights into the mechanisms underlying hematopoietic suppression in response to leukemic cell outgrowth and offer new strategies to further improve current therapies for leukemias, placing more emphasis on the augmentation of normal hematopoietic regeneration when targeting leukemic cells.
Research Grants
|
Grant Number (Funded) |
Grant Title |
Role in Project and Percentage of Effort |
Years Inclusive |
Source $ Amount |
|
2016YFA0100600 |
Development, maintenance, and regeneration mechanisms of hematopoietic stem cells |
Principal Investigator 33% |
01/16-12/20 |
Ministry of Science and Technology of China: $4,615,385 |
|
91519315 |
The study of new epigenetic factors regulating PUMA expression during blood cells reprogramming toward iPSCs. |
Principal Investigator 100% |
01/16-12/16 |
National Natural Science Foundation of China: $135,385 |
|
81421002 |
Regulatory and regeneration mechanisms of hematopoietic stem cells |
Principal Investigator 30% |
01/15-12/20 |
National Natural Science Foundation of China: $1,846,154 |