Background

M.D. / Ph.D.  Genetics, Shanghai Second Medical University, 2004
M.S.  Immunology, Shandong Academy of Medical Sciences, 2001
B.S.  Clinical Medicine, Taishan Medical University, 1998

Postdoctoral Fellowship 
Maine Medical Center Research Institute, 2009
Cincinnati Children’s Hospital Medical Center, 2016

Research Interests

Hematopoiesis is a highly hierarchical process that multipotential hematopoietic stem cells (HSCs) give rise to all the mature blood cells. The research in my laboratory is to understand the molecular mechanisms governing hematopoiesis with animal models, and how dysregulated signaling pathways in HSC may drive hematological malignancies with a focus on myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). We are currently studying on two molecules, an adaptor protein sequestosome 1 (also known as p62) and a G protein-coupled receptor GPR68, and their functions in hematopoiesis, HSC function and leukemogenesis. Our long-term goal is to uncover novel mechanisms driving malignant hematopoiesis and identify novel therapeutic targets of hematological malignancies.

p62 is an adaptor protein, containing multiple protein-protein interaction domains that form a signaling scaffold. Through interactions with specific proteins, p62 regulates downstream signaling pathways necessary for distinct cellular functions, such as apoptosis, cell survival, autophagy, metabolism and aging. Previous studies implicate p62 as dispensable for normal hematopoietic stem and progenitor cell (HSPC) function. Intriguingly we find that p62 is overexpressed in leukemia cells. RNAi-mediated knockdown of p62 in leukemia cell lines correlates with massive apoptosis, reduced cell growth and reduced leukemia progenitor cell function. Based on these observations, we hypothesize that hematopoietic cells acquire a dependency on p62 during transformation. To test this hypothesis, we apply genetic loss of function approach to determine the contribution of p62 to leukemia initiation and leukemia maintenance. In addition, we identify cell and molecular mechanism by which p62 utilizes to promote leukemia development. We also examine therapeutic potential by targeting the p62 signaling pathway in leukemia.

GPR68 is a transmembrane protein that, upon ligand binding, associates with G proteins, Gq/11 or Gs, activating phospholipase C-b (PLCb)/calcium (Ca²⁺) or adenylyl cyclase (AC)/cyclic AMP (cAMP) signaling pathways, respectively. Our previous study implicates GPR68 in determining sensitivity to lenalidomide in MDS. To determine the function of GPR68 in normal hematopoiesis, we utilize a genetic loss of function approach and find reduced output of B lymphocytes in whole body Gpr68 knockout mice upon aging or hematopoietic regeneration. With the same mouse model, we found no alterations on HSC function either under steady state or upon stress. To determine the function of GPR68 in leukemia, we deplete GPR68 expression in leukemia cells and find massive cell death, and significantly reduced cell growth. Currently, we are trying to understand the role of GPR68 in leukemogenesis, and to identify the mechanism of GPR68 to promote leukemia. We also plan to explore therapeutic potential by targeting the GPR68 pathway as a means of eradicating leukemia cells and leukemia stem cells.

Selected Publications

Dou A, Fang J. Cyclosporine broadens the therapeutic potential of lenalidomide in myeloid malignancies. J Cell Immunol. 2020:2(5):237-244. PMID: 32984863 

He X, Hawkins C, Lawley L, Freeman K, Phan TM, Zhang J, Xu Y, Fang J. Whole body deletion of Gpr68 does not change hematopoietic stem cell function. Stem Cell Res. 2020 Jun 20;47:101869. PMID: 32592951 

He X, Dou A, Feng S, Roman-Rivera A, Hawkins C, Lawley L, Zhang J, Wunderlich M, Mizukawa B, Halene S, Patel A, Fang J. Cyclosporine enhances the sensitivity to lenalidomide in MDS/AML in vitro. Exp Hematol. 2020 Jun;86:21-27.e2. PMID: 32437909 

He X, Feng S, Hawkins C, Lawley L, Fan W, Xu Y, Zha XM, Fang J. G protein-coupled receptor 68 increases the number of B lymphocytes. Am J Blood Res. Am J Blood Res. 2020 Apr 15;10(2):15-21. eCollection 2020. PMID: 32411498

Fang J, Muto T, Kleppe M, Bolanos LC, Hueneman KM, Walker CS, Sampson L, Wellendorf AM, Chetal K, Choi K, Salomonis N, Choi Y, Zheng Y, Cancelas JA, Levine RL, Starczynowski DT. TRAF6 mediates basal activation of NF-kB necessary for hematopoietic stem cell homeostasis. Cell Rep. 2018 Jun 30;22(5):1250-1262. PMID: 29386112

Fang J, Bolanos LC, Choi K, Liu X, Christie S, Akunuru S, Kumar R, Wang D, Chen X, Greis KD, Stoilov P, Filippi MD, Maciejewski JP, Garcia-Manero G, Weirauch MT, Salomonis N, Geiger H, Zheng Y, Starczynowski DT. Ubiquitination of hnRNPA1 by TRAF6 links chronic innate immune signaling with myelodysplasia. Nat Immunol. 2017 Feb;18(2):236-245. PMID: 28024152

Fang J, Liu X, Bolanos L, Barker B, Rigolino C, Cortelezzi A, Oliva EN, Cuzzola M, Grimes HL, Fontanillo C, Komurov K, MacBeth K, Starczynowski DT. A calcium- and calpain-dependent pathway determines the response to lenalidomide in myelodysplastic syndromes. Nat Med, 2016 Jul;22(7):724-34. PMID: 27294874

Fang J, Starczynowski DT. Genomic instability establishes dependencies on acquired gene regulatory networks: a novel role of p62 in myeloid malignancies with del(5q). Mol Cell Oncol. 2015 Oct-Dec;2(4):e1014219. PMID: 27308507

Fang J, Barker B, Bolanos L, Liu X, Jerez A, Makishima H, Christie S, Chen X, Rao DS, Grimes HL, Komurov K, Weirauch MT, Cancelas JA, Maciejewski JP, Starczynowski DT. Myeloid malignancies with chromosome 5q deletions acquire a dependency on an intrachromosomal NF-kB gene network. Cell Rep. 2014 Sep 11;8(5):1328-38. PMID: 25199827 

Fang J, Rhyasen G, Bolanos L, Rasch C, Varney M, Wunderlich M, Goyama S, Jansen G, Cloos J, Rigolino C, Cortelezzi A, Mulloy JC, Oliva EN, Cuzzola M, Starczynowski DT. Cytotoxic effects of bortezomib in myelodysplastic syndrome/acute myeloid leukemia depend on autophagy-mediated lysosomal degradation of TRAF6 and repression of PSMA1. Blood. 2012 Jul 26;120(4):858-67. PMID: 22685174 

Fang J, Varney M, Starczynowski DT. Implication of microRNAs in the pathogenesis of MDS. Curr Pharm Des. 2012;18(22):3170-9. Review. PMID: 22571695 

Dev A*, Fang J*, Sathyanarayana P, Pradeep A, Emerson C, Wojchowski DM. During EPO or anemia challenge, erythroid progenitor cells transit through a selectively expandable proerythroblast pool. Blood. 2010 Dec 9;116(24):5334-46. PMID: 20810925 (*equally contributed) 

Fang J, Menon M, Zhang D, Torbett B, Oxburgh L, Tschan M, Houde E, Wojchowski DM. Attenuation of EPO-dependent erythroblast formation by death-associated protein kinase-2. Blood. 2008 Aug 1;112(3):886-90. PMID: 18535204 

Fang J, Menon M, Kapelle W, Bogacheva O, Bogachev O, Houde E, Browne S, Sathyanarayana P, Wojchowski DM. EPO modulation of cell-cycle regulatory genes, and cell division, in primary bone marrow erythroblasts. Blood. 2007 Oct 1;110(7):2361-70. PMID: 17548578 

Shen ZX*, Shi ZZ*, Fang J*, Gu BW, Li JM, Zhu YM, Shi JY, Zheng PZ, Yan H, Liu YF, Chen Y, Shen Y, Wu W, Tang W, Waxman S, De Thé H, Wang ZY, Chen SJ, Chen Z. All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5328-35. PMID: 15044693 (*equally contributed)

Fang J, Chen SJ, Tong JH, Wang ZG, Chen GQ, Chen Z. Treatment of acute promyelocytic leukemia with ATRA and As2O3: a model of molecular target-based cancer therapy. Cancer Biol Ther. 2002 Nov-Dec;1(6):614-20. Review. PMID: 12642682

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