Dr. Zhao received his M.D. from China Medical University (Shenyang, China) in 1993 and Ph.D. from Keio University School of Medicine (Tokyo, Japan) in 2002. He conducted his postdoctoral research in Dr. Tannishtha Reya’s laboratory at Duke University Medical Center, where he demonstrated the important roles of the Wnt and Hedgehog signaling pathways in regulating the self-renewal of chronic myeloid leukemia stem cells. He became a physician-scientist (assistant professor) in the Department of Pathology at the University of Iowa in 2014. In addition to fulfill his clinical service as a hematopathologist, he has been focusing on developing basic and translational research programs exploring novel signaling pathways in hematologic malignancies. He was promoted to an associate professor with tenure before leaving UIOWA. He joined in the Department of Pathology at CWRU in August 2020.
We are focusing on seeking in-depth understanding of the mechanisms of hematopoietic stem/progenitor cell (HSPC) self-renewal, the interactions of HSPCs and bone marrow microenvironment, and how these become dysregulated to cause leukemia/lymphoma. Specifically, we are focusing on 1) How HSF1 specifically regulates AML stem cells; and 2) how B-myeloid conversion is regulated in a pathological context.
Zhao lab is focusing on seeking in-depth understanding of the mechanisms of hematopoietic stem/progenitor cell (HSPC) self-renewal, the interactions of HSPCs and bone marrow microenvironment, and how these become dysregulated to cause leukemia/lymphoma. Specifically, we are focusing on 1) How HSF1 specifically regulates AML stem cells; and 2) how B-myeloid conversion is regulated in a pathological context.
HSF1 in hematopoietic stem cell and leukemic stem cell self-renewal: Acute myeloid leukemia (AML) is maintained by self-renewing leukemic stem cells (LSCs). A fundamental problem in treating AML is that conventional therapy fails to eliminate LSCs, which can reinitiate leukemia. Heat shock transcription factor 1 (HSF1), a central regulator of the stress response, has emerged as an important target in cancer therapy. Using genetic Hsf1 deletion and a direct HSF1 small molecule inhibitor, we show that HSF1 is specifically required for the maintenance of AML, while sparing steady-state and stressed hematopoiesis. Importantly, the nuclear expression of HSF1 protein correlated with AML patient status and could serve as a clinical marker to monitor AML progression. We are focusing on testing different HSF1 inhibitors in different subtypes of human AMLs.
NF-kB/Notch coactivation-induced B cell lymphoma and B cell plasticity: We have demonstrated that NF-kB/Notch-coactivated marginal zone precursor B cells transform to overt lymphoma de novo, but convert to myeloid lineage after transplantation through dedifferentiation, and some (15%) further transform to myeloid leukemia with clonal IGH gene rearrangement, suggesting that marginal zone precursors are the common lymphoid and myeloid neoplasm progenitors in this model. In addition, DNA hypermethylation is required for the maintenance of converted myeloid leukemia as DNA demethylating drug (decitabine) kills most leukemia cells. Importantly, we identify the common lymphoid and myeloid leukemia progenitors and shared IGH gene rearrangements in concurrent human lymphoid and myeloid leukemias. We are focusing on investigating the underlying molecular mechanisms.
Zhao C, Irie N, Takada Y, Shimoda K, Miyamoto T, Nishiwaki T, Ishikawa H, Suda T, Matsuo K. Bidirectional ephrinB2-EphB4 signaling controls bone homeostasis. Cell Metabolism. 2006 4: 111–121.
Zhao C, Blum J, Chen A, Kwon HY, Jung SH, Cook JM, Lagoo A, Reya T. Loss of b-catenin impairs the renewal of normal and CML stem cells in vivo. Cancer Cell. 2007 12: 528–541.
Zhao C, Chen A, Fereshteh M, Abrahamsson A, Blum J, Kwon HY, Kim J, Chute JP, Rizzieri D, VanArsdale T, Jamieson CH, Beachy PA, Reya T. Hedgehog signaling is essential for maintenance of cancer stem cells in chronic myelogenous leukemia. Nature. 2009 458: 776–779.
Xiu Y, Xue WY, Lambertz A, Leidinger M, Gibson-Corley K, Zhao C. Constitutive Activation of NIK Impairs the Self-Renewal of Hematopoietic Stem/Progenitor Cells and Induces Bone Marrow Failure. Stem Cells. 2017 35:777-786.
Li F, He B, Ma X, Yu S, Roy R, Lentz SR, Tan K, Guzman ML, Zhao C*, Xue HH*. Prostaglandin E1 and Its Analog Misoprostol Inhibit Human CML Stem Cell Self-Renewal via EP4 Receptor Activation and Repression of AP-1. Cell Stem Cell. 2017 21: 359-373.e5.
* co-corresponding authors.
Xiu Y, Dong Q, Li Q, Li F, Borcherding N, Zhang W, Boyce B, Xue HH, Zhao C. Stabilization of NF-kB-Inducing Kinase Suppresses MLL-AF9-Induced Acute Myeloid Leukemia. Cell Rep. 2018 22:350-358.
Xiu Y, Dong QZ, Fu L, Bossler A, Tang XB,1 Boyce BF, Borcherding N, Leidinger M, Sardina J, Xue HH, Li QC, Feldman A, Aifantis I, Boccalatte F, Wang LL, Jin ML, Khoury J, Wang W, Hu SM, Yuan YZ, Wang ED, Yuan J, Janz S, Colgan J, Habelhah H, Waldschmidt T, Muschen M, Bagg A, Darbro B and Zhao C. Coactivation of NF-kB and Notch signaling is sufficient to induce B cell transformation and enables B-myeloid conversion. Blood. 2020;135:108-120.
Dong Q, Xiu Y, Bossler A, Syrbu S, Wang H, Xue W, Zhao J, Li Q, Jin M, Wang L, Boyce B, Sakr H, Ansari MQ, Zhao C. CLL dedifferentiation to clonally related myeloid cells. Blood Advances. 2020; 4:6169-6174.
Zhao J, Xiu Y, Fu L, Dong Q, Borcherding N, Wang Y, Li Q, De Silva NS, Klein U, Boyce BF, Zhao C. TIFAB accelerates MLL-AF9-Induced acute myeloid leukemia through upregulation of HOXA9. iScience. 2021 Dec 17;24(12):103425. doi: 10.1016/j.isci.2021.103425.
Dong Q, Xiu Y, Wang Y, Hodgson C, Borcherding, N, Jordan CT, Buchanan J, Taylor E, Wagner B, Leidinger M, Holman C, Thiele DJ, O’Brien S, Xue HH, Zhao J, Li Q, Meyerson H, Boyce BF, Zhao C. HSF1 is a Driver of Leukemia Stem Cell Self-Renewal in Acute Myeloid Leukemia. Nature Communications. 2022 in press.