Demin Wang, PhD
Senior Investigator, Versiti Blood Research Institute; Assistant Professor
- Microbiology & Immunology
During hematopoiesis, hematopoietic stem cells (HSCs) give rise to all blood cells, including erythroid, myeloid and lymphoid lineages. The self-renewal and hematopoietic differentiation of HSCs are strictly controlled by both extrinsic and intrinsic signals. B cells, a subtype of lymphoid cells, are critical to the immune defense, and their development and function are also highly regulated by signals derived from a variety of cell surface receptors. Abnormal signals from the receptors often lead to hematological and immunological diseases, including hematopoietic malignancies, and immunodeficiency and autoimmune diseases. Our research focuses on identifying and functionally characterizing signaling pathways that control B cell development from hematopoietic stem cells (HSCs) and B cell function. Our research employs multiple cutting-edge approaches, including targeted gene disruption, transgenic, bone marrow transplantation and high-throughput DNA/RNA sequencing technologies.
Cytokine receptor signaling
Upon binding of cytokines, cytokine receptors initiate signals to regulate a variety of cellular responses, including cell growth, survival, differentiation, and function during hematopoiesis. Engagement of cytokine receptors induces the activation of the JAK family of cytoplasmic protein tyrosine kinases. In turn, Jaks activate components of diverse signal transduction pathways, including members of the Signal Transducers and Activators of Transcription (Stat). The importance of the JAKs and Stats in signaling has been emphasized by gene disruption studies. Dysregulation of JAK/Stat pathway has been implicated in the pathogenesis of numerous hematological diseases. One of our current research projects studies the regulation and function of Stat proteins.
B cell receptor signaling
B cells are one important component of the adaptive immune system. Signals from the B cell antigen receptor (BCR) and its surrogate predecessor pre-BCR are essential for the development, maintenance and function of B cells. Improper signals from pre-BCR/BCR often result in immunodeficiency, autoimmunity, and B-cell leukemia. During last decade, a wide variety of signaling molecules involved in BCR function have been discovered. Our current research projects aim to fully understand the pre-BCR/BCR signal transduction cascade by identifying novel signaling molecules of the pre-BCR/BCR and investigate the roles of these signaling molecules in pre-BCR/BCR-mediated B cell development and function in vivo.
The long term goals of our research program aim to establish a thorough understanding of the normal signaling pathways of the cytokine and pre-BCR/BCR receptors, to obtain new clues regarding the molecular pathogenesis of numerous hematological and immunological diseases, including acute or chronic hematopoietic malignancies, and immunodeficiency (such as agammaglobulinemia and common variable immunodeficiency) and autoimmune (such as systemic lupus erythematosus, rheumatoid arthritis, type I diabetes, multiple sclerosis, hemolytic anemia, and heparin-induced thrombocytopenia) diseases, and to aid in the development of novel therapeutic strategies for treatment of these hematological and immunological disorders.
Expression of NrasQ61R and MYC transgene in germinal center B cells induces a highly malignant multiple myeloma in mice.
(Wen Z, Rajagopalan A, Flietner ED, Yun G, Chesi M, Furumo Q, Burns RT, Papadas A, Ranheim EA, Pagenkopf AC, Morrow ZT, Finn R, Zhou Y, Li S, You X, Jensen J, Yu M, Cicala A, Menting J, Mitsiades CS, Callander NS, Bergsagel PL, Wang D, Asimakopoulos F, Zhang J.) Blood. 2021 Jan 07;137(1):61-74 PMID: 32640012 PMCID: PMC7808014 SCOPUS ID: 2-s2.0-85099107626 07/09/2020
Kras-Deficient T Cells Attenuate Graft-versus-Host Disease but Retain Graft-versus-Leukemia Activity.
(Luo L, Chen Y, Chen X, Zheng Y, Zhou V, Yu M, Burns R, Zhu W, Fu G, Felix JC, Hartley C, Damnernsawad A, Zhang J, Wen R, Drobyski WR, Gao C, Wang D.) J Immunol. 2020 Dec 15;205(12):3480-3490 PMID: 33158956 PMCID: PMC7955895 SCOPUS ID: 2-s2.0-85097490484 11/08/2020
BAD inactivation exacerbates rheumatoid arthritis pathology by promoting survival of sublining macrophages.
(Li J, Zhang L, Zheng Y, Shao R, Liang Q, Yu W, Wang H, Zou W, Wang D, Xiang J, Lin A.) Elife. 2020 Dec 03;9 PMID: 33270017 PMCID: PMC7714394 SCOPUS ID: 2-s2.0-85097125352 12/04/2020
Hemostasis vs. homeostasis: Platelets are essential for preserving vascular barrier function in the absence of injury or inflammation.
(Gupta S, Konradt C, Corken A, Ware J, Nieswandt B, Di Paola J, Yu M, Wang D, Nieman MT, Whiteheart SW, Brass LF.) Proc Natl Acad Sci U S A. 2020 Sep 29;117(39):24316-24325 PMID: 32929010 PMCID: PMC7533880 SCOPUS ID: 2-s2.0-85092289547 09/16/2020
Transcriptional Regulation of Natural Killer Cell Development and Functions.
(Wang D, Malarkannan S.) Cancers (Basel). 2020 Jun 16;12(6) PMID: 32560225 PMCID: PMC7352776 06/21/2020
Single-cell transcriptome reveals the novel role of T-bet in suppressing the immature NK gene signature.
(Yang C, Siebert JR, Burns R, Zheng Y, Mei A, Bonacci B, Wang D, Urrutia RA, Riese MJ, Rao S, Carlson KS, Thakar MS, Malarkannan S.) Elife. 2020 May 14;9 PMID: 32406817 PMCID: PMC7255804 SCOPUS ID: 2-s2.0-85085630468 05/15/2020
Mirc11 Disrupts Inflammatory but Not Cytotoxic Responses of NK Cells.
(Nanbakhsh A, Srinivasamani A, Holzhauer S, Riese MJ, Zheng Y, Wang D, Burns R, Reimer MH, Rao S, Lemke A, Tsaih SW, Flister MJ, Lao S, Dahl R, Thakar MS, Malarkannan S.) Cancer Immunol Res. 2019 Oct;7(10):1647-1662 PMID: 31515257 PMCID: PMC7428857 SCOPUS ID: 2-s2.0-85072848720 09/14/2019
Regulatory T Cells Control PF4/Heparin Antibody Production in Mice.
(Zheng Y, Zhu W, Haribhai D, Williams CB, Aster RH, Wen R, Wang D.) J Immunol. 2019 Oct 01;203(7):1786-1792 PMID: 31471526 PMCID: PMC6944762 SCOPUS ID: 2-s2.0-85072761081 09/01/2019
Altered Nuclear Export Signal Recognition as a Driver of Oncogenesis.
(Taylor J, Sendino M, Gorelick AN, Pastore A, Chang MT, Penson AV, Gavrila EI, Stewart C, Melnik EM, Herrejon Chavez F, Bitner L, Yoshimi A, Lee SC, Inoue D, Liu B, Zhang XJ, Mato AR, Dogan A, Kharas MG, Chen Y, Wang D, Soni RK, Hendrickson RC, Prieto G, Rodriguez JA, Taylor BS, Abdel-Wahab O.) Cancer Discov. 2019 Oct;9(10):1452-1467 PMID: 31285298 PMCID: PMC6774834 SCOPUS ID: 2-s2.0-85071298982 07/10/2019
CXCR5+PD-1+ follicular helper CD8 T cells control B cell tolerance.
(Chen Y, Yu M, Zheng Y, Fu G, Xin G, Zhu W, Luo L, Burns R, Li QZ, Dent AL, Zhu N, Cui W, Malherbe L, Wen R, Wang D.) Nat Commun. 2019 Sep 27;10(1):4415 PMID: 31562329 PMCID: PMC6765049 SCOPUS ID: 2-s2.0-85072692451 09/29/2019
Immune-Checkpoint Protein VISTA Regulates Antitumor Immunity by Controlling Myeloid Cell-Mediated Inflammation and Immunosuppression.
(Xu W, Dong J, Zheng Y, Zhou J, Yuan Y, Ta HM, Miller HE, Olson M, Rajasekaran K, Ernstoff MS, Wang D, Malarkannan S, Wang L.) Cancer Immunol Res. 2019 Sep;7(9):1497-1510 PMID: 31340983 PMCID: PMC6726548 SCOPUS ID: 2-s2.0-85071783703 07/26/2019
Critical role of Jumonji domain of JMJD1C in MLL-rearranged leukemia.
(Izaguirre-Carbonell J, Christiansen L, Burns R, Schmitz J, Li C, Mokry RL, Bluemn T, Zheng Y, Shen J, Carlson KS, Rao S, Wang D, Zhu N.) Blood Adv. 2019 May 14;3(9):1499-1511 PMID: 31076406 PMCID: PMC6517669 SCOPUS ID: 2-s2.0-85068626845 05/12/2019