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

Haley E. Ramsey; Kristy Stengel; James C. Pino; Gretchen Johnston; Merrida Childress; Agnieszka E. Gorska; Pia M. Arrate; Londa Fuller; Matthew Villaume; Melissa A. Fischer; P. Brent Ferrell; Caroline E. Roe; Jing Zou; Alexander L.R. Lubbock; Matthew Stubbs; Sandra Zinkel; Jonathan M. Irish; Carlos F. Lopez; Scott Hiebert; Michael R. Savona

doi:10.1007/s11523-021-00830-5

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

Haley E. Ramsey, Kristy Stengel, James C. Pino, Gretchen Johnston, Merrida Childress, Agnieszka E. Gorska, Pia M. Arrate, Londa Fuller, Matthew Villaume, Melissa A. Fischer, P. Brent Ferrell, Caroline E. Roe, Jing Zou, Alexander L.R. Lubbock, Matthew Stubbs, Sandra Zinkel, Jonathan M. Irish, Carlos F. Lopez, Scott Hiebert, Michael R. Savona

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

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.

Original language	English (US)
Pages (from-to)	663-674
Number of pages	12
Journal	Targeted Oncology
Volume	16
Issue number	5
DOIs	https://doi.org/10.1007/s11523-021-00830-5
State	Published - Sep 2021
Externally published	Yes

ASJC Scopus subject areas

Oncology
Cancer Research
Pharmacology (medical)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1007/s11523-021-00830-5

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Ramsey, H. E., Stengel, K., Pino, J. C., Johnston, G., Childress, M., Gorska, A. E., Arrate, P. M., Fuller, L., Villaume, M., Fischer, M. A., Ferrell, P. B., Roe, C. E., Zou, J., Lubbock, A. L. R., Stubbs, M., Zinkel, S., Irish, J. M., Lopez, C. F., Hiebert, S., & Savona, M. R. (2021). Selective Inhibition of JAK1 Primes STAT5-Driven Human Leukemia Cells for ATRA-Induced Differentiation. Targeted Oncology, 16(5), 663-674. https://doi.org/10.1007/s11523-021-00830-5

Ramsey, HE, Stengel, K, Pino, JC, Johnston, G, Childress, M, Gorska, AE, Arrate, PM, Fuller, L, Villaume, M, Fischer, MA, Ferrell, PB, Roe, CE, Zou, J, Lubbock, ALR, Stubbs, M, Zinkel, S, Irish, JM, Lopez, CF, Hiebert, S & Savona, MR 2021, 'Selective Inhibition of JAK1 Primes STAT5-Driven Human Leukemia Cells for ATRA-Induced Differentiation', Targeted Oncology, vol. 16, no. 5, pp. 663-674. https://doi.org/10.1007/s11523-021-00830-5

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title = "Selective Inhibition of JAK1 Primes STAT5-Driven Human Leukemia Cells for ATRA-Induced Differentiation",

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.",

author = "Ramsey, {Haley E.} and Kristy Stengel and Pino, {James C.} and Gretchen Johnston and Merrida Childress and Gorska, {Agnieszka E.} and Arrate, {Pia M.} and Londa Fuller and Matthew Villaume and Fischer, {Melissa A.} and Ferrell, {P. Brent} and Roe, {Caroline E.} and Jing Zou and Lubbock, {Alexander L.R.} and Matthew Stubbs and Sandra Zinkel and Irish, {Jonathan M.} and Lopez, {Carlos F.} and Scott Hiebert and Savona, {Michael R.}",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature Switzerland AG.",

year = "2021",

month = sep,

doi = "10.1007/s11523-021-00830-5",

language = "English (US)",

volume = "16",

pages = "663--674",

journal = "Targeted Oncology",

issn = "1776-2596",

publisher = "Springer Paris",

number = "5",

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TY - JOUR

T1 - Selective Inhibition of JAK1 Primes STAT5-Driven Human Leukemia Cells for ATRA-Induced Differentiation

AU - Ramsey, Haley E.

AU - Stengel, Kristy

AU - Pino, James C.

AU - Johnston, Gretchen

AU - Childress, Merrida

AU - Gorska, Agnieszka E.

AU - Arrate, Pia M.

AU - Fuller, Londa

AU - Villaume, Matthew

AU - Fischer, Melissa A.

AU - Ferrell, P. Brent

AU - Roe, Caroline E.

AU - Zou, Jing

AU - Lubbock, Alexander L.R.

AU - Stubbs, Matthew

AU - Zinkel, Sandra

AU - Irish, Jonathan M.

AU - Lopez, Carlos F.

AU - Hiebert, Scott

AU - Savona, Michael R.

PY - 2021/9

Y1 - 2021/9

N2 - 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.

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

Abstract

ASJC Scopus subject areas

UN SDGs

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