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 journalArticle

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 languageEnglish (US)
Pages (from-to)362-675
Number of pages314
JournalCancer Discovery
Volume4
Issue number3
DOIs
StatePublished - Mar 2014
Externally publishedYes

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B-Cell Leukemia
B-Cell Lymphoma
Acute Myeloid Leukemia
Cell Death
Mitochondria
Biomarkers
Clinical Trials
Myeloid Cells
B-Cell Chronic Lymphocytic Leukemia
Heterografts
2-(4'-diethylaminophenyl)benzothiazole
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(1H-pyrrolo(2,3-b)pyridin-5-yloxy)benzamide
Neoplasms
Cell Line

ASJC Scopus subject areas

  • Oncology

Cite this

Pan, R., Hogdal, L. J., Benito, J. M., Bucci, D., Han, L., Borthakur, 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

Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid Leukemia. / Pan, Rongqing; Hogdal, Leah J.; Benito, Juliana M.; Bucci, Donna; Han, Lina; Borthakur, Gautam; Cortes, Jorge; Deangelo, Daniel J.; Debose, Lakeisha; Mu, Hong; Döhner, Hartmut; Gaidzik, Verena I.; Galinsky, Ilene; Golfman, Leonard S.; Haferlach, Torsten; Harutyunyan, Karine G.; Hu, Jianhua; Leverson, Joel D.; Marcucci, Guido; Müschen, Markus; Newman, Rachel; Park, Eugene; Ruvolo, Peter P.; Ruvolo, Vivian; Ryan, Jeremy; Schindela, Sonja; Zweidler-Mckay, Patrick; Stone, Richard M.; Kantarjian, Hagop; Andreeff, Michael; Konopleva, Marina; Letai, Anthony G.

In: Cancer Discovery, Vol. 4, No. 3, 03.2014, p. 362-675.

Research output: Contribution to journalArticle

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
Pan, Rongqing ; Hogdal, Leah J. ; Benito, Juliana M. ; Bucci, Donna ; Han, Lina ; Borthakur, Gautam ; Cortes, Jorge ; Deangelo, Daniel J. ; Debose, Lakeisha ; Mu, Hong ; Döhner, Hartmut ; Gaidzik, Verena I. ; Galinsky, Ilene ; Golfman, Leonard S. ; Haferlach, Torsten ; Harutyunyan, Karine G. ; Hu, Jianhua ; Leverson, Joel D. ; Marcucci, Guido ; Müschen, Markus ; Newman, Rachel ; Park, Eugene ; Ruvolo, Peter P. ; Ruvolo, Vivian ; Ryan, Jeremy ; Schindela, Sonja ; Zweidler-Mckay, Patrick ; Stone, Richard M. ; Kantarjian, Hagop ; Andreeff, Michael ; Konopleva, Marina ; Letai, Anthony G. / Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid Leukemia. In: Cancer Discovery. 2014 ; Vol. 4, No. 3. pp. 362-675.
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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.",
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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.

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