Ras oncogene-independent activation of RALB signaling is a targetable mechanism of escape from NRAS(V12) oncogene addiction in acute myeloid leukemia

E. J. Pomeroy, L. A. Lee, R. D W Lee, D. K. Schirm, N. A. Temiz, J. Ma, T. A. Gruber, E. Diaz-Flores, B. S. Moriarity, J. R. Downing, K. M. Shannon, D. A. Largaespada, C. E. Eckfeldt

Research output: Contribution to journalArticle

Abstract

Somatic mutations that lead to constitutive activation of NRAS and KRAS proto-oncogenes are among the most common in human cancer and frequently occur in acute myeloid leukemia (AML). An inducible NRAS(V12)-driven AML mouse model has established a critical role for continued NRAS(V12) expression in leukemia maintenance. In this model genetic suppression of NRAS(V12) expression results in rapid leukemia remission, but some mice undergo spontaneous relapse with NRAS(V12)-independent (NRI) AMLs providing an opportunity to identify mechanisms that bypass the requirement for Ras oncogene activity and drive leukemia relapse. We found that relapsed NRI AMLs are devoid of NRAS(V12) expression and signaling through the major oncogenic Ras effector pathways, phosphatidylinositol-3-kinase and mitogen-activated protein kinase, but express higher levels of an alternate Ras effector, Ralb, and exhibit NRI phosphorylation of the RALB effector TBK1, implicating RALB signaling in AML relapse. Functional studies confirmed that inhibiting CDK5-mediated RALB activation with a clinically relevant experimental drug, dinaciclib, led to potent RALB-dependent antileukemic effects in human AML cell lines, induced apoptosis in patient-derived AML samples in vitro and led to a 2-log reduction in the leukemic burden in patient-derived xenograft mice. Furthermore, dinaciclib potently suppressed the clonogenic potential of relapsed NRI AMLs in vitro and prevented the development of relapsed AML in vivo. Our findings demonstrate that Ras oncogene-independent activation of RALB signaling is a therapeutically targetable mechanism of escape from NRAS oncogene addiction in AML.

Original languageEnglish (US)
Pages (from-to)3263-3273
Number of pages11
JournalOncogene
Volume36
Issue number23
DOIs
StatePublished - Jun 8 2017

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ras Genes
Oncogenes
Acute Myeloid Leukemia
Leukemia
Recurrence
Phosphatidylinositol 3-Kinase
Genetic Suppression
Proto-Oncogenes
Myeloid Cells
Mitogen-Activated Protein Kinases
Heterografts
Maintenance
Phosphorylation
Apoptosis
Cell Line
Mutation
Pharmaceutical Preparations
Neoplasms

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Ras oncogene-independent activation of RALB signaling is a targetable mechanism of escape from NRAS(V12) oncogene addiction in acute myeloid leukemia. / Pomeroy, E. J.; Lee, L. A.; Lee, R. D W; Schirm, D. K.; Temiz, N. A.; Ma, J.; Gruber, T. A.; Diaz-Flores, E.; Moriarity, B. S.; Downing, J. R.; Shannon, K. M.; Largaespada, D. A.; Eckfeldt, C. E.

In: Oncogene, Vol. 36, No. 23, 08.06.2017, p. 3263-3273.

Research output: Contribution to journalArticle

Pomeroy, E. J. ; Lee, L. A. ; Lee, R. D W ; Schirm, D. K. ; Temiz, N. A. ; Ma, J. ; Gruber, T. A. ; Diaz-Flores, E. ; Moriarity, B. S. ; Downing, J. R. ; Shannon, K. M. ; Largaespada, D. A. ; Eckfeldt, C. E. / Ras oncogene-independent activation of RALB signaling is a targetable mechanism of escape from NRAS(V12) oncogene addiction in acute myeloid leukemia. In: Oncogene. 2017 ; Vol. 36, No. 23. pp. 3263-3273.
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AU - Pomeroy, E. J.

AU - Lee, L. A.

AU - Lee, R. D W

AU - Schirm, D. K.

AU - Temiz, N. A.

AU - Ma, J.

AU - Gruber, T. A.

AU - Diaz-Flores, E.

AU - Moriarity, B. S.

AU - Downing, J. R.

AU - Shannon, K. M.

AU - Largaespada, D. A.

AU - Eckfeldt, C. E.

PY - 2017/6/8

Y1 - 2017/6/8

N2 - Somatic mutations that lead to constitutive activation of NRAS and KRAS proto-oncogenes are among the most common in human cancer and frequently occur in acute myeloid leukemia (AML). An inducible NRAS(V12)-driven AML mouse model has established a critical role for continued NRAS(V12) expression in leukemia maintenance. In this model genetic suppression of NRAS(V12) expression results in rapid leukemia remission, but some mice undergo spontaneous relapse with NRAS(V12)-independent (NRI) AMLs providing an opportunity to identify mechanisms that bypass the requirement for Ras oncogene activity and drive leukemia relapse. We found that relapsed NRI AMLs are devoid of NRAS(V12) expression and signaling through the major oncogenic Ras effector pathways, phosphatidylinositol-3-kinase and mitogen-activated protein kinase, but express higher levels of an alternate Ras effector, Ralb, and exhibit NRI phosphorylation of the RALB effector TBK1, implicating RALB signaling in AML relapse. Functional studies confirmed that inhibiting CDK5-mediated RALB activation with a clinically relevant experimental drug, dinaciclib, led to potent RALB-dependent antileukemic effects in human AML cell lines, induced apoptosis in patient-derived AML samples in vitro and led to a 2-log reduction in the leukemic burden in patient-derived xenograft mice. Furthermore, dinaciclib potently suppressed the clonogenic potential of relapsed NRI AMLs in vitro and prevented the development of relapsed AML in vivo. Our findings demonstrate that Ras oncogene-independent activation of RALB signaling is a therapeutically targetable mechanism of escape from NRAS oncogene addiction in AML.

AB - Somatic mutations that lead to constitutive activation of NRAS and KRAS proto-oncogenes are among the most common in human cancer and frequently occur in acute myeloid leukemia (AML). An inducible NRAS(V12)-driven AML mouse model has established a critical role for continued NRAS(V12) expression in leukemia maintenance. In this model genetic suppression of NRAS(V12) expression results in rapid leukemia remission, but some mice undergo spontaneous relapse with NRAS(V12)-independent (NRI) AMLs providing an opportunity to identify mechanisms that bypass the requirement for Ras oncogene activity and drive leukemia relapse. We found that relapsed NRI AMLs are devoid of NRAS(V12) expression and signaling through the major oncogenic Ras effector pathways, phosphatidylinositol-3-kinase and mitogen-activated protein kinase, but express higher levels of an alternate Ras effector, Ralb, and exhibit NRI phosphorylation of the RALB effector TBK1, implicating RALB signaling in AML relapse. Functional studies confirmed that inhibiting CDK5-mediated RALB activation with a clinically relevant experimental drug, dinaciclib, led to potent RALB-dependent antileukemic effects in human AML cell lines, induced apoptosis in patient-derived AML samples in vitro and led to a 2-log reduction in the leukemic burden in patient-derived xenograft mice. Furthermore, dinaciclib potently suppressed the clonogenic potential of relapsed NRI AMLs in vitro and prevented the development of relapsed AML in vivo. Our findings demonstrate that Ras oncogene-independent activation of RALB signaling is a therapeutically targetable mechanism of escape from NRAS oncogene addiction in AML.

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