Haley E Ramsey1,2, Kristy Stengel3, James C Pino3,4, Gretchen Johnston3, Merrida Childress2, Agnieszka E Gorska2, Pia M Arrate2, Londa Fuller1, Matthew Villaume1,2, Melissa A Fischer1,2, P Brent Ferrell1,2, Caroline E Roe5,6, Jing Zou2,5, Alexander L R Lubbock3,4, Matthew Stubbs7, Sandra Zinkel1,2,5,8, Jonathan M Irish5,6, Carlos F Lopez3,4, Scott Hiebert2,3,8, Michael R Savona9,10,11,12. 1. Cancer Biology Program, Vanderbilt University School of Medicine, Nashville, TN, USA. 2. Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA. 3. Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA. 4. Department of Bioinformatics, Vanderbilt University School of Medicine, Nashville, TN, USA. 5. Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA. 6. Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA. 7. Incyte Research Institute, Wilmington, DE, USA. 8. Division of Hematology/Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 777 Preston Research Building, 2200 Pierce Avenue, Nashville, TN, 37232, USA. 9. Cancer Biology Program, Vanderbilt University School of Medicine, Nashville, TN, USA. michael.savona@vanderbilt.edu. 10. Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA. michael.savona@vanderbilt.edu. 11. Vanderbilt Center for Immunobiology, Nashville, TN, USA. michael.savona@vanderbilt.edu. 12. 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.
Abstract
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.
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.
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