Dependence of peripheral T-cell lymphoma on constitutively activated JAK3: Implication for JAK3 inhibition as a therapeutic approach

Kang Le, Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, George Washington University, GW Cancer Center, Washington, District of Columbia, USA.
Jordan Vollenweider, Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, George Washington University, GW Cancer Center, Washington, District of Columbia, USA.
JingJing Han, Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA.
Nicholas Staudinger, Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, George Washington University, GW Cancer Center, Washington, District of Columbia, USA.
Mary Stenson, Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA.
Lara Bayraktar, Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, George Washington University, GW Cancer Center, Washington, District of Columbia, USA.
Linda E. Wellik, Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA.
Matthew J. Maurer, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.
Ellen D. McPhail, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
Thomas E. Witzig, Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA.
Mamta Gupta, Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, George Washington University, GW Cancer Center, Washington, District of Columbia, USA.

Document Type

Journal Article

Publication Date

10-24-2023

Journal

Hematological oncology

DOI

10.1002/hon.3233

Keywords

ALK; JAK3 inhibitors; PTCL; PTPN11; pJAK3

Abstract

Peripheral T-cell lymphoma (PTCL) is a clinically heterogeneous group that represents 10%-15% of all lymphomas. Despite improved genetic and molecular understanding, treatment outcomes for PTCL have not shown significant improvement. Although Janus kinase-2 (JAK2) plays an important role in myeloproliferative neoplasms, the critical role of JAK isoforms in mediating prosurvival signaling in PTCL cells is not well defined. Immunohistochemical analysis of PTCL tumors (n = 96) revealed high levels of constitutively active JAK3 (pJAK3) that significantly (p < 0.04) correlated with the activation state of its canonical substrate STAT3. Furthermore, constitutive activation of JAK3 and STAT3 positively correlated, at least in part, with an oncogenic tyrosine phosphatase PTPN11. Pharmacological inhibition of JAK3 but not JAK1/JAK2 significantly (p < 0.001) decreased PTCL proliferation, survival and STAT3 activation. A sharp contrast was observed in the pJAK3 positivity between ALK+ (85.7%) versus ALK-negative (10.0%) in human PTCL tumors and PTCL cell lines. Moreover, JAK3 and ALK reciprocally interacted in PTCL cells, forming a complex to possibly regulate STAT3 signaling. Finally, combined inhibition of JAK3 (by WHI-P154) and ALK (by crizotinib or alectinib) significantly (p < 0.01) decreased the survival of PTCL cells as compared to either agent alone by inhibiting STAT3 downstream signaling. Collectively, our findings establish that JAK3 is a therapeutic target for a subset of PTCL, and provide rationale for the clinical evaluation of JAK3 inhibitors combined with ALK-targeted therapy in PTCL.

Department

Biochemistry and Molecular Medicine

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