Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid Leukemia

Rongqing Pan; Leah J. Hogdal; Juliana M. Benito; Donna Bucci; Lina Han; Gautam Borthakur; Jorge Cortes; Daniel J. Deangelo; Lakeisha Debose; Hong Mu; Hartmut Döhner; Verena I. Gaidzik; Ilene Galinsky; Leonard S. Golfman; Torsten Haferlach; Karine G. Harutyunyan; Jianhua Hu; Joel D. Leverson; Guido Marcucci; Markus Müschen; Rachel Newman; Eugene Park; Peter P. Ruvolo; Vivian Ruvolo; Jeremy Ryan; Sonja Schindela; Patrick Zweidler-Mckay; Richard M. Stone; Hagop Kantarjian; Michael Andreeff; Marina Konopleva; Anthony G. Letai

doi:10.1158/2159-8290.CD-13-0609

Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid Leukemia

Rongqing Pan, Leah J. Hogdal, Juliana M. Benito, Donna Bucci, Lina Han, Gautam Borthakur, Jorge Cortes, Daniel J. Deangelo, Lakeisha Debose, Hong Mu, Hartmut Döhner, Verena I. Gaidzik, Ilene Galinsky, Leonard S. Golfman, Torsten Haferlach, Karine G. Harutyunyan, Jianhua Hu, Joel D. Leverson, Guido Marcucci, Markus MüschenRachel Newman, Eugene Park, Peter P. Ruvolo, Vivian Ruvolo, Jeremy Ryan, Sonja Schindela, Patrick Zweidler-Mckay, Richard M. Stone, Hagop Kantarjian, Michael Andreeff, Marina Konopleva, Anthony G. Letai

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

537 Scopus citations

Abstract

B-cell leukemia/lymphoma 2 (BCL-2) prevents commitment to programmed cell death at the mitochondrion. It remains a challenge to identify those tumors that are best treated by inhibition of BCL-2. Here, we demonstrate that acute myeloid leukemia (AML) cell lines, primary patient samples, and murine primary xenografts are very sensitive to treatment with the selective BCL-2 antagonist ABT-199. In primary patient cells, the median IC ₅₀ was approximately 10 nmol/L, and cell death occurred within 2 hours. Our ex vivo sensitivity results compare favorably with those observed for chronic lymphocytic leukemia, a disease for which ABT-199 has demonstrated consistent activity in clinical trials. Moreover, mitochondrial studies using BH3 profi ling demonstrate activity at the mitochondrion that correlates well with cytotoxicity, supporting an on-target mitochondrial mechanism of action. Our protein and BH3 profiling studies provide promising tools that can be tested as predictive biomarkers in any clinical trial of ABT-199 in AML. SIGNIFICANCE: Although targeting BCL-2 has largely been investigated in lymphoid cancers, we present preclinical results of targeting BCL-2 in AML. These results support clinical testing of the small-molecule BCL-2 antagonist ABT-199 in AML, accompanied by testing of predictive biomarkers used in this study.

Original language	English (US)
Pages (from-to)	362-675
Number of pages	314
Journal	Cancer Discovery
Volume	4
Issue number	3
DOIs	https://doi.org/10.1158/2159-8290.CD-13-0609
State	Published - Mar 2014
Externally published	Yes

ASJC Scopus subject areas

Oncology

UN SDGs

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

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10.1158/2159-8290.CD-13-0609

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Pan, R., Hogdal, L. J., Benito, J. M., Bucci, D., Han, L., Borthakur, G., Cortes, J., Deangelo, D. J., Debose, L., Mu, H., Döhner, H., Gaidzik, V. I., Galinsky, I., Golfman, L. S., Haferlach, T., Harutyunyan, K. G., Hu, J., Leverson, J. D., Marcucci, G., ... Letai, A. G. (2014). Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid Leukemia. Cancer Discovery, 4(3), 362-675. https://doi.org/10.1158/2159-8290.CD-13-0609

Pan, R, Hogdal, LJ, Benito, JM, Bucci, D, Han, L, Borthakur, G, Cortes, J, Deangelo, DJ, Debose, L, Mu, H, Döhner, H, Gaidzik, VI, Galinsky, I, Golfman, LS, Haferlach, T, Harutyunyan, KG, Hu, J, Leverson, JD, Marcucci, G, Müschen, M, Newman, R, Park, E, Ruvolo, PP, Ruvolo, V, Ryan, J, Schindela, S, Zweidler-Mckay, P, Stone, RM, Kantarjian, H, Andreeff, M, Konopleva, M & Letai, AG 2014, 'Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid Leukemia', Cancer Discovery, vol. 4, no. 3, pp. 362-675. https://doi.org/10.1158/2159-8290.CD-13-0609

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title = "Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid Leukemia",

abstract = "B-cell leukemia/lymphoma 2 (BCL-2) prevents commitment to programmed cell death at the mitochondrion. It remains a challenge to identify those tumors that are best treated by inhibition of BCL-2. Here, we demonstrate that acute myeloid leukemia (AML) cell lines, primary patient samples, and murine primary xenografts are very sensitive to treatment with the selective BCL-2 antagonist ABT-199. In primary patient cells, the median IC 50 was approximately 10 nmol/L, and cell death occurred within 2 hours. Our ex vivo sensitivity results compare favorably with those observed for chronic lymphocytic leukemia, a disease for which ABT-199 has demonstrated consistent activity in clinical trials. Moreover, mitochondrial studies using BH3 profi ling demonstrate activity at the mitochondrion that correlates well with cytotoxicity, supporting an on-target mitochondrial mechanism of action. Our protein and BH3 profiling studies provide promising tools that can be tested as predictive biomarkers in any clinical trial of ABT-199 in AML. SIGNIFICANCE: Although targeting BCL-2 has largely been investigated in lymphoid cancers, we present preclinical results of targeting BCL-2 in AML. These results support clinical testing of the small-molecule BCL-2 antagonist ABT-199 in AML, accompanied by testing of predictive biomarkers used in this study.",

author = "Rongqing Pan and Hogdal, {Leah J.} and Benito, {Juliana M.} and Donna Bucci and Lina Han and Gautam Borthakur and Jorge Cortes and Deangelo, {Daniel J.} and Lakeisha Debose and Hong Mu and Hartmut D{\"o}hner and Gaidzik, {Verena I.} and Ilene Galinsky and Golfman, {Leonard S.} and Torsten Haferlach and Harutyunyan, {Karine G.} and Jianhua Hu and Leverson, {Joel D.} and Guido Marcucci and Markus M{\"u}schen and Rachel Newman and Eugene Park and Ruvolo, {Peter P.} and Vivian Ruvolo and Jeremy Ryan and Sonja Schindela and Patrick Zweidler-Mckay and Stone, {Richard M.} and Hagop Kantarjian and Michael Andreeff and Marina Konopleva and Letai, {Anthony G.}",

year = "2014",

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doi = "10.1158/2159-8290.CD-13-0609",

language = "English (US)",

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T1 - Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid Leukemia

AU - Pan, Rongqing

AU - Hogdal, Leah J.

AU - Benito, Juliana M.

AU - Bucci, Donna

AU - Han, Lina

AU - Borthakur, Gautam

AU - Cortes, Jorge

AU - Deangelo, Daniel J.

AU - Debose, Lakeisha

AU - Mu, Hong

AU - Döhner, Hartmut

AU - Gaidzik, Verena I.

AU - Galinsky, Ilene

AU - Golfman, Leonard S.

AU - Haferlach, Torsten

AU - Harutyunyan, Karine G.

AU - Hu, Jianhua

AU - Leverson, Joel D.

AU - Marcucci, Guido

AU - Müschen, Markus

AU - Newman, Rachel

AU - Park, Eugene

AU - Ruvolo, Peter P.

AU - Ruvolo, Vivian

AU - Ryan, Jeremy

AU - Schindela, Sonja

AU - Zweidler-Mckay, Patrick

AU - Stone, Richard M.

AU - Kantarjian, Hagop

AU - Andreeff, Michael

AU - Konopleva, Marina

AU - Letai, Anthony G.

PY - 2014/3

Y1 - 2014/3

N2 - B-cell leukemia/lymphoma 2 (BCL-2) prevents commitment to programmed cell death at the mitochondrion. It remains a challenge to identify those tumors that are best treated by inhibition of BCL-2. Here, we demonstrate that acute myeloid leukemia (AML) cell lines, primary patient samples, and murine primary xenografts are very sensitive to treatment with the selective BCL-2 antagonist ABT-199. In primary patient cells, the median IC 50 was approximately 10 nmol/L, and cell death occurred within 2 hours. Our ex vivo sensitivity results compare favorably with those observed for chronic lymphocytic leukemia, a disease for which ABT-199 has demonstrated consistent activity in clinical trials. Moreover, mitochondrial studies using BH3 profi ling demonstrate activity at the mitochondrion that correlates well with cytotoxicity, supporting an on-target mitochondrial mechanism of action. Our protein and BH3 profiling studies provide promising tools that can be tested as predictive biomarkers in any clinical trial of ABT-199 in AML. SIGNIFICANCE: Although targeting BCL-2 has largely been investigated in lymphoid cancers, we present preclinical results of targeting BCL-2 in AML. These results support clinical testing of the small-molecule BCL-2 antagonist ABT-199 in AML, accompanied by testing of predictive biomarkers used in this study.

AB - B-cell leukemia/lymphoma 2 (BCL-2) prevents commitment to programmed cell death at the mitochondrion. It remains a challenge to identify those tumors that are best treated by inhibition of BCL-2. Here, we demonstrate that acute myeloid leukemia (AML) cell lines, primary patient samples, and murine primary xenografts are very sensitive to treatment with the selective BCL-2 antagonist ABT-199. In primary patient cells, the median IC 50 was approximately 10 nmol/L, and cell death occurred within 2 hours. Our ex vivo sensitivity results compare favorably with those observed for chronic lymphocytic leukemia, a disease for which ABT-199 has demonstrated consistent activity in clinical trials. Moreover, mitochondrial studies using BH3 profi ling demonstrate activity at the mitochondrion that correlates well with cytotoxicity, supporting an on-target mitochondrial mechanism of action. Our protein and BH3 profiling studies provide promising tools that can be tested as predictive biomarkers in any clinical trial of ABT-199 in AML. SIGNIFICANCE: Although targeting BCL-2 has largely been investigated in lymphoid cancers, we present preclinical results of targeting BCL-2 in AML. These results support clinical testing of the small-molecule BCL-2 antagonist ABT-199 in AML, accompanied by testing of predictive biomarkers used in this study.

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SN - 2159-8274

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ER -

Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid Leukemia

Abstract

ASJC Scopus subject areas

UN SDGs

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