Selective Inhibition of JAK1 Primes STAT5-Driven Human Leukemia Cells for ATRA-Induced Differentiation.

Autor:	Ramsey HE; Cancer Biology Program, Vanderbilt University School of Medicine, Nashville, TN, USA.; Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA., Stengel K; Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA., Pino JC; Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA.; Department of Bioinformatics, Vanderbilt University School of Medicine, Nashville, TN, USA., Johnston G; Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA., Childress M; Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA., Gorska AE; Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA., Arrate PM; Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA., Fuller L; Cancer Biology Program, Vanderbilt University School of Medicine, Nashville, TN, USA., Villaume M; Cancer Biology Program, Vanderbilt University School of Medicine, Nashville, TN, USA.; Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA., Fischer MA; Cancer Biology Program, Vanderbilt University School of Medicine, Nashville, TN, USA.; Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA., Ferrell PB Jr; Cancer Biology Program, Vanderbilt University School of Medicine, Nashville, TN, USA.; Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA., Roe CE; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.; Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA., Zou J; Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA., Lubbock ALR; Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA.; Department of Bioinformatics, Vanderbilt University School of Medicine, Nashville, TN, USA., Stubbs M; Incyte Research Institute, Wilmington, DE, USA., Zinkel S; Cancer Biology Program, Vanderbilt University School of Medicine, Nashville, TN, USA.; Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.; Division of Hematology/Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 777 Preston Research Building, 2200 Pierce Avenue, Nashville, TN, 37232, USA., Irish JM; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.; Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA., Lopez CF; Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA.; Department of Bioinformatics, Vanderbilt University School of Medicine, Nashville, TN, USA., Hiebert S; Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.; Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA.; Division of Hematology/Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 777 Preston Research Building, 2200 Pierce Avenue, Nashville, TN, 37232, USA., Savona MR; Cancer Biology Program, Vanderbilt University School of Medicine, Nashville, TN, USA. michael.savona@vanderbilt.edu.; Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA. michael.savona@vanderbilt.edu.; Vanderbilt Center for Immunobiology, Nashville, TN, USA. michael.savona@vanderbilt.edu.; Division of Hematology/Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 777 Preston Research Building, 2200 Pierce Avenue, Nashville, TN, 37232, USA. michael.savona@vanderbilt.edu.
Jazyk:	angličtina
Zdroj:	Targeted oncology [Target Oncol] 2021 Sep; Vol. 16 (5), pp. 663-674. Date of Electronic Publication: 2021 Jul 29.
DOI:	10.1007/s11523-021-00830-5
Abstrakt:	Background: All-trans retinoic acid (ATRA), a derivate of vitamin A, has been successfully used as a therapy to induce differentiation in M3 acute promyelocytic leukemia (APML), and has led to marked improvement in outcomes. Previously, attempts to use ATRA in non-APML in the clinic, however, have been underwhelming, likely due to persistent signaling through other oncogenic drivers. Dysregulated JAK/STAT signaling is known to drive several hematologic malignancies, and targeting JAK1 and JAK2 with the JAK1/JAK2 inhibitor ruxolitinib has led to improvement in survival in primary myelofibrosis and alleviation of vasomotor symptoms and splenomegaly in polycythemia vera and myelofibrosis. Objective: While dose-dependent anemia and thrombocytopenia limit the use of JAK2 inhibition, selectively targeting JAK1 has been explored as a means to suppress inflammation and STAT-associated pathologies related to neoplastogenesis. The objective of this study is to employ JAK1 inhibition (JAK1i) in the presence of ATRA as a potential therapy in non-M3 acute myeloid leukemia (AML). Methods: Efficacy of JAK1i using INCB52793 was assessed by changes in cell cycle and apoptosis in treated AML cell lines. Transcriptomic and proteomic analysis evaluated effects of JAK1i. Synergy between JAK1i+ ATRA was assessed in cell lines in vitro while efficacy in vivo was assessed by tumor reduction in MV-4-11 cell line-derived xenografts. Results: Here we describe novel synergistic activity between JAK1i inhibition and ATRA in non-M3 leukemia. Transcriptomic and proteomic analysis confirmed structural and functional changes related to maturation while in vivo combinatory studies revealed significant decreases in leukemic expansion. Conclusions: JAK1i+ ATRA lead to decreases in cell cycle followed by myeloid differentiation and cell death in human leukemias. These findings highlight potential uses of ATRA-based differentiation therapy of non-M3 human leukemia. (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)
Databáze:	MEDLINE
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