MEK inhibition enhances ABT-737-induced leukemia cell apoptosis via prevention of ERK-activated MCL-1 induction and modulation of MCL-1/BIM complex

M. Konopleva, M. Milella, P. Ruvolo, J. C. Watts, M. R. Ricciardi, B. Korchin, T. McQueen, W. Bornmann, T. Tsao, P. Bergamo, D. H. Mak, W. Chen, J. McCubrey, A. Tafuri, M. Andreeff

Research output: Contribution to journalArticle

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Abstract

Recently, strategies for acute myeloid leukemia (AML) therapy have been developed that target anti-apoptotic BCL2 family members using BH3-mimetic drugs such as ABT-737. Though effective against BCL2 and BCL-X L, ABT-737 poorly inhibits MCL-1. Here we report that, unexpectedly, ABT-737 induces activation of the extracellular receptor activated kinase and induction of MCL-1 in AML cells. MEK inhibitors such as PD0325901 and CI-1040 have been used successfully to suppress MCL-1. We report that PD0325901 blocked ABT-737-induced MCL-1 expression, and when combined with ABT-737 resulted in potent synergistic killing of AML-derived cell lines, primary AML blast and CD34+38-123+ progenitor/stem cells. Finally, we tested the combination of ABT-737 and CI-1040 in a murine xenograft model using MOLM-13 human leukemia cells.Whereas control mice and CI-1040-treated mice exhibited progressive leukemia growth, ABT-737, and to a significantly greater extent, ABT-737+CI-1040 exerted major anti-leukemia activity. Collectively, results demonstrated unexpected anti-apoptotic interaction between the BCL2 family-targeted BH3-mimetic ABT-737 and mitogen-activated protein kinase signaling in AML cells: the BH3 mimetic is not only restrained in its activity by MCL-1, but also induces its expression. However, concomitant inhibition by BH3 mimetics and MEK inhibitors could abrogate this effect and may be developed into a novel and effective therapeutic strategy for patients with AML.

Original languageEnglish (US)
Pages (from-to)778-787
Number of pages10
JournalLeukemia
Volume26
Issue number4
DOIs
StatePublished - Apr 2012

Fingerprint

Mitogen-Activated Protein Kinase Kinases
Leukemia
Apoptosis
Acute Myeloid Leukemia
Myeloid Cells
Stem Cells
Inhibition (Psychology)
ABT-737
Mitogen-Activated Protein Kinases
Heterografts
Phosphotransferases
Cell Line
2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide
Therapeutics
Growth

Keywords

  • ABT-737
  • AML
  • apoptosis
  • BH3 mimetic
  • ERK
  • MCL-1

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

Cite this

Konopleva, M., Milella, M., Ruvolo, P., Watts, J. C., Ricciardi, M. R., Korchin, B., ... Andreeff, M. (2012). MEK inhibition enhances ABT-737-induced leukemia cell apoptosis via prevention of ERK-activated MCL-1 induction and modulation of MCL-1/BIM complex. Leukemia, 26(4), 778-787. https://doi.org/10.1038/leu.2011.287

MEK inhibition enhances ABT-737-induced leukemia cell apoptosis via prevention of ERK-activated MCL-1 induction and modulation of MCL-1/BIM complex. / Konopleva, M.; Milella, M.; Ruvolo, P.; Watts, J. C.; Ricciardi, M. R.; Korchin, B.; McQueen, T.; Bornmann, W.; Tsao, T.; Bergamo, P.; Mak, D. H.; Chen, W.; McCubrey, J.; Tafuri, A.; Andreeff, M.

In: Leukemia, Vol. 26, No. 4, 04.2012, p. 778-787.

Research output: Contribution to journalArticle

Konopleva, M, Milella, M, Ruvolo, P, Watts, JC, Ricciardi, MR, Korchin, B, McQueen, T, Bornmann, W, Tsao, T, Bergamo, P, Mak, DH, Chen, W, McCubrey, J, Tafuri, A & Andreeff, M 2012, 'MEK inhibition enhances ABT-737-induced leukemia cell apoptosis via prevention of ERK-activated MCL-1 induction and modulation of MCL-1/BIM complex', Leukemia, vol. 26, no. 4, pp. 778-787. https://doi.org/10.1038/leu.2011.287
Konopleva, M. ; Milella, M. ; Ruvolo, P. ; Watts, J. C. ; Ricciardi, M. R. ; Korchin, B. ; McQueen, T. ; Bornmann, W. ; Tsao, T. ; Bergamo, P. ; Mak, D. H. ; Chen, W. ; McCubrey, J. ; Tafuri, A. ; Andreeff, M. / MEK inhibition enhances ABT-737-induced leukemia cell apoptosis via prevention of ERK-activated MCL-1 induction and modulation of MCL-1/BIM complex. In: Leukemia. 2012 ; Vol. 26, No. 4. pp. 778-787.
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abstract = "Recently, strategies for acute myeloid leukemia (AML) therapy have been developed that target anti-apoptotic BCL2 family members using BH3-mimetic drugs such as ABT-737. Though effective against BCL2 and BCL-X L, ABT-737 poorly inhibits MCL-1. Here we report that, unexpectedly, ABT-737 induces activation of the extracellular receptor activated kinase and induction of MCL-1 in AML cells. MEK inhibitors such as PD0325901 and CI-1040 have been used successfully to suppress MCL-1. We report that PD0325901 blocked ABT-737-induced MCL-1 expression, and when combined with ABT-737 resulted in potent synergistic killing of AML-derived cell lines, primary AML blast and CD34+38-123+ progenitor/stem cells. Finally, we tested the combination of ABT-737 and CI-1040 in a murine xenograft model using MOLM-13 human leukemia cells.Whereas control mice and CI-1040-treated mice exhibited progressive leukemia growth, ABT-737, and to a significantly greater extent, ABT-737+CI-1040 exerted major anti-leukemia activity. Collectively, results demonstrated unexpected anti-apoptotic interaction between the BCL2 family-targeted BH3-mimetic ABT-737 and mitogen-activated protein kinase signaling in AML cells: the BH3 mimetic is not only restrained in its activity by MCL-1, but also induces its expression. However, concomitant inhibition by BH3 mimetics and MEK inhibitors could abrogate this effect and may be developed into a novel and effective therapeutic strategy for patients with AML.",
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AU - Bornmann, W.

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AU - Bergamo, P.

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