uppression of multiple anti-apoptotic BCL2 family proteins recapitulates the effects of JAK2 inhibitors in JAK2V617F driven myeloproliferative neoplasm

Author(s):Show less -

Takei, Hisashi ^{[1, 2, 3]} ; Coelho-Silva, Juan Luiz ^[4] ; Leal, Cristina Tavares ^[4] ; Arantes Rocha, Adriana Queiroz ^[5] ; Bianco, Thiago Mantello ^[4] ; Welner, Robert S. ^[6] ; Mishima, Yuta ^[7] ; Kobayashi, Ikei S. ^{[1, 2]} ; Mullally, Ann ^[8] ; Lima, Keli ^[9] ; Machado-Neto, Joao Agostinho ^[9] ; Kobayashi, Susumu S. ^{[1, 10, 2, 11]} ; de Figueiredo-Pontes, Lorena Lobo ^[4]

Affiliation:Show less -

^[1] Harvard Med Sch, Boston, MA 02115 - USA

^[2] Beth Israel Deaconess Med Ctr, Dept Med, E-CLS 407, 330 Brookline Ave, Boston, MA 02215 - USA

^[3] Gunma Univ, Dept Hematol, Grad Sch Med, Maebashi, Gumma - Japan

^[4] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Med Images Hematol & Clin Oncol, BR-14049900 Ribeirao Preto, SP - Brazil

^[5] Fed Univ Jatai, Special Hlth Sci Acad Unit, Jatai - Brazil

^[6] Univ Alabama Birmingham, Dept Med, Div Hematol Oncol, Birmingham, AL 35294 - USA

^[7] Univ Tsukuba, Fac Med, Transborder Med Res Ctr, Dept Clin Med, Tsukuba, Ibaraki - Japan

^[8] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Div Hematol, Boston, MA 02115 - USA

^[9] Univ Sao Paulo, Inst Biomed Sci, Dept Pharmacol, BR-05508900 Sao Paulo - Brazil

^[10] Harvard Med Sch, Harvard Stem Cell Inst, Boston, MA 02115 - USA

^[11] Natl Canc Ctr, Exploratory Oncol Res & Clin Trial Ctr, Div Translat Genom, Kashiwa, Chiba - Japan

• Document type: Journal article
• Source: Cancer Science; v. 113, n. 2 DEC 2021.
• Web of Science Citations: 0

Abstract

Several lines of research suggest that Bcl-xL-mediated anti-apoptotic effects may contribute to the pathogenesis of myeloproliferative neoplasms driven by JAK2V617F and serve as therapeutic target. Here, we used a knock-in JAK2V617F mouse model and confirmed that Bcl-xL was overexpressed in erythroid progenitors. The myeloproliferative neoplasm (MPN)-induced phenotype in the peripheral blood by conditional knock-in of JAK2V617F was abrogated by conditional knockout of Bcl2l1, which presented anemia and thrombocytopenia independently of JAK2 mutation status. Mx1-Cre Jak2V617(W/VF)/Bcl2l1(f/f) mice presented persistent splenomegaly as a result of extramedullary hematopoiesis and pro-apoptotic stimuli in terminally differentiated erythroid progenitors. The pan-BH3 mimetic inhibitor obatoclax showed superior cytotoxicity in JAK2V617F cell models, and reduced clonogenic capacity in ex vivo assay using Vav-Cre Jak2V617F bone marrow cells. Both ruxolitinib and obatoclax significantly reduced spleen weights in a murine Jak2V617F MPN model but did not show additive effect. The tumor burden reduction was observed with either ruxolitinib or obatoclax in terminal differentiation stage neoplastic cells but not in myeloid-erythroid precursors. Therefore, disrupting the BCL2 balance is not sufficient to treat MPN at the stem cell level, but it is certainly an additional option for controlling the critical myeloid expansion of the disease. (AU)

• FAPESP's process: 11/11822-6 - Analysis of the gene expression profile of acute myeloid leukemia subtypes with C/EBPA genetic abnormalities
• Grantee: Lorena Lôbo de Figueiredo Pontes
• Support Opportunities: Scholarships abroad - Research
• FAPESP's process: 15/21866-1 - Cytokine-mediated regulation of normal and neoplastic hematopoietic stem cells by natural killer cells
• Grantee: Lorena Lôbo de Figueiredo Pontes
• Support Opportunities: Research Grants - Young Investigators Grants