BCL-2 family proteins as 5-Azacytidine-sensitizing targets and determinants of response in myeloid malignancies

J. M. Bogenberger; S. M. Kornblau; W. E. Pierceall; R. Lena; D. Chow; C. X. Shi; J. Mantei; G. Ahmann; I. M. Gonzales; A. Choudhary; R. Valdez; J. Camoriano; V. Fauble; R. E. Tiedemann; Y. H. Qiu; K. R. Coombes; M. Cardone; E. Braggio; H. Yin; D. O. Azorsa; R. A. Mesa; A. K. Stewart; R. Tibes

doi:10.1038/leu.2014.44

BCL-2 family proteins as 5-Azacytidine-sensitizing targets and determinants of response in myeloid malignancies

J. M. Bogenberger, S. M. Kornblau, W. E. Pierceall, R. Lena, D. Chow, C. X. Shi, J. Mantei, G. Ahmann, I. M. Gonzales, A. Choudhary, R. Valdez, J. Camoriano, V. Fauble, R. E. Tiedemann, Y. H. Qiu, K. R. Coombes, M. Cardone, E. Braggio, H. Yin, D. O. AzorsaR. A. Mesa, A. K. Stewart, R. Tibes

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

166 Scopus citations

Abstract

Synergistic molecular vulnerabilities enhancing hypomethylating agents in myeloid malignancies have remained elusive. RNA-interference drug modifier screens identified antiapoptotic BCL-2 family members as potent 5-Azacytidine-sensitizing targets. In further dissecting BCL-X_L, BCL-2 and MCL-1 contribution to 5-Azacytidine activity, siRNA silencing of BCL-X_L and MCL-1, but not BCL-2, exhibited variable synergy with 5-Azacytidine in vitro. The BCL-X_L, BCL-2 and BCL-w inhibitor ABT-737 sensitized most cell lines more potently compared with the selective BCL-2 inhibitor ABT-199, which synergized with 5-Azacytidine mostly at higher doses. Ex vivo, ABT-737 enhanced 5-Azacytidine activity across primary AML, MDS and MPN specimens. Protein levels of BCL-X_L, BCL-2 and MCL-1 in 577 AML patient samples showed overlapping expression across AML FAB subtypes and heterogeneous expression within subtypes, further supporting a concept of dual/multiple BCL-2 family member targeting consistent with RNAi and pharmacologic results. Consequently, silencing of MCL-1 and BCL-X_L increased the activity of ABT-199. Functional interrogation of BCL-2 family proteins by BH3 profiling performed on patient samples significantly discriminated clinical response versus resistance to 5-Azacytidine-based therapies. On the basis of these results, we propose a clinical trial of navitoclax (clinical-grade ABT-737) combined with 5-Azacytidine in myeloid malignancies, as well as to prospectively validate BH3 profiling in predicting 5-Azacytidine response.

Original language	English (US)
Pages (from-to)	1657-1665
Number of pages	9
Journal	Leukemia
Volume	28
Issue number	8
DOIs	https://doi.org/10.1038/leu.2014.44
State	Published - Aug 2014
Externally published	Yes

Keywords

5-Azacytidine
BH3 profiling
myeloid malignancies

ASJC Scopus subject areas

Hematology
Oncology
Cancer Research

UN SDGs

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

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10.1038/leu.2014.44

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Bogenberger, J. M., Kornblau, S. M., Pierceall, W. E., Lena, R., Chow, D., Shi, C. X., Mantei, J., Ahmann, G., Gonzales, I. M., Choudhary, A., Valdez, R., Camoriano, J., Fauble, V., Tiedemann, R. E., Qiu, Y. H., Coombes, K. R., Cardone, M., Braggio, E., Yin, H., ... Tibes, R. (2014). BCL-2 family proteins as 5-Azacytidine-sensitizing targets and determinants of response in myeloid malignancies. Leukemia, 28(8), 1657-1665. https://doi.org/10.1038/leu.2014.44

Bogenberger, JM, Kornblau, SM, Pierceall, WE, Lena, R, Chow, D, Shi, CX, Mantei, J, Ahmann, G, Gonzales, IM, Choudhary, A, Valdez, R, Camoriano, J, Fauble, V, Tiedemann, RE, Qiu, YH, Coombes, KR, Cardone, M, Braggio, E, Yin, H, Azorsa, DO, Mesa, RA, Stewart, AK & Tibes, R 2014, 'BCL-2 family proteins as 5-Azacytidine-sensitizing targets and determinants of response in myeloid malignancies', Leukemia, vol. 28, no. 8, pp. 1657-1665. https://doi.org/10.1038/leu.2014.44

@article{4ae52413569041aba6b193bd976d4279,

title = "BCL-2 family proteins as 5-Azacytidine-sensitizing targets and determinants of response in myeloid malignancies",

abstract = "Synergistic molecular vulnerabilities enhancing hypomethylating agents in myeloid malignancies have remained elusive. RNA-interference drug modifier screens identified antiapoptotic BCL-2 family members as potent 5-Azacytidine-sensitizing targets. In further dissecting BCL-XL, BCL-2 and MCL-1 contribution to 5-Azacytidine activity, siRNA silencing of BCL-XL and MCL-1, but not BCL-2, exhibited variable synergy with 5-Azacytidine in vitro. The BCL-XL, BCL-2 and BCL-w inhibitor ABT-737 sensitized most cell lines more potently compared with the selective BCL-2 inhibitor ABT-199, which synergized with 5-Azacytidine mostly at higher doses. Ex vivo, ABT-737 enhanced 5-Azacytidine activity across primary AML, MDS and MPN specimens. Protein levels of BCL-XL, BCL-2 and MCL-1 in 577 AML patient samples showed overlapping expression across AML FAB subtypes and heterogeneous expression within subtypes, further supporting a concept of dual/multiple BCL-2 family member targeting consistent with RNAi and pharmacologic results. Consequently, silencing of MCL-1 and BCL-XL increased the activity of ABT-199. Functional interrogation of BCL-2 family proteins by BH3 profiling performed on patient samples significantly discriminated clinical response versus resistance to 5-Azacytidine-based therapies. On the basis of these results, we propose a clinical trial of navitoclax (clinical-grade ABT-737) combined with 5-Azacytidine in myeloid malignancies, as well as to prospectively validate BH3 profiling in predicting 5-Azacytidine response.",

keywords = "5-Azacytidine, BH3 profiling, myeloid malignancies",

author = "Bogenberger, {J. M.} and Kornblau, {S. M.} and Pierceall, {W. E.} and R. Lena and D. Chow and Shi, {C. X.} and J. Mantei and G. Ahmann and Gonzales, {I. M.} and A. Choudhary and R. Valdez and J. Camoriano and V. Fauble and Tiedemann, {R. E.} and Qiu, {Y. H.} and Coombes, {K. R.} and M. Cardone and E. Braggio and H. Yin and Azorsa, {D. O.} and Mesa, {R. A.} and Stewart, {A. K.} and R. Tibes",

note = "Funding Information: This work was supported in part by American Cancer Society Postdoctoral Fellowship Grant 119364-PF-10-123-01 awarded to JMB, in part by a grant from the IBIS Foundation for Individualized Medicine awarded to RT, in part by a Mayo Clinic Career Development award to RT, and in part by NCI-SBIR #HHSN261201200039C and #HHSN261201299985C contracts to Eutropics Pharmaceuticals. Institutional support was provided by TGen and Mayo Clinic.",

year = "2014",

month = aug,

doi = "10.1038/leu.2014.44",

language = "English (US)",

volume = "28",

pages = "1657--1665",

journal = "Leukemia",

issn = "0887-6924",

publisher = "Nature Publishing Group",

number = "8",

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TY - JOUR

T1 - BCL-2 family proteins as 5-Azacytidine-sensitizing targets and determinants of response in myeloid malignancies

AU - Bogenberger, J. M.

AU - Kornblau, S. M.

AU - Pierceall, W. E.

AU - Lena, R.

AU - Chow, D.

AU - Shi, C. X.

AU - Mantei, J.

AU - Ahmann, G.

AU - Gonzales, I. M.

AU - Choudhary, A.

AU - Valdez, R.

AU - Camoriano, J.

AU - Fauble, V.

AU - Tiedemann, R. E.

AU - Qiu, Y. H.

AU - Coombes, K. R.

AU - Cardone, M.

AU - Braggio, E.

AU - Yin, H.

AU - Azorsa, D. O.

AU - Mesa, R. A.

AU - Stewart, A. K.

AU - Tibes, R.

N1 - Funding Information: This work was supported in part by American Cancer Society Postdoctoral Fellowship Grant 119364-PF-10-123-01 awarded to JMB, in part by a grant from the IBIS Foundation for Individualized Medicine awarded to RT, in part by a Mayo Clinic Career Development award to RT, and in part by NCI-SBIR #HHSN261201200039C and #HHSN261201299985C contracts to Eutropics Pharmaceuticals. Institutional support was provided by TGen and Mayo Clinic.

PY - 2014/8

Y1 - 2014/8

N2 - Synergistic molecular vulnerabilities enhancing hypomethylating agents in myeloid malignancies have remained elusive. RNA-interference drug modifier screens identified antiapoptotic BCL-2 family members as potent 5-Azacytidine-sensitizing targets. In further dissecting BCL-XL, BCL-2 and MCL-1 contribution to 5-Azacytidine activity, siRNA silencing of BCL-XL and MCL-1, but not BCL-2, exhibited variable synergy with 5-Azacytidine in vitro. The BCL-XL, BCL-2 and BCL-w inhibitor ABT-737 sensitized most cell lines more potently compared with the selective BCL-2 inhibitor ABT-199, which synergized with 5-Azacytidine mostly at higher doses. Ex vivo, ABT-737 enhanced 5-Azacytidine activity across primary AML, MDS and MPN specimens. Protein levels of BCL-XL, BCL-2 and MCL-1 in 577 AML patient samples showed overlapping expression across AML FAB subtypes and heterogeneous expression within subtypes, further supporting a concept of dual/multiple BCL-2 family member targeting consistent with RNAi and pharmacologic results. Consequently, silencing of MCL-1 and BCL-XL increased the activity of ABT-199. Functional interrogation of BCL-2 family proteins by BH3 profiling performed on patient samples significantly discriminated clinical response versus resistance to 5-Azacytidine-based therapies. On the basis of these results, we propose a clinical trial of navitoclax (clinical-grade ABT-737) combined with 5-Azacytidine in myeloid malignancies, as well as to prospectively validate BH3 profiling in predicting 5-Azacytidine response.

AB - Synergistic molecular vulnerabilities enhancing hypomethylating agents in myeloid malignancies have remained elusive. RNA-interference drug modifier screens identified antiapoptotic BCL-2 family members as potent 5-Azacytidine-sensitizing targets. In further dissecting BCL-XL, BCL-2 and MCL-1 contribution to 5-Azacytidine activity, siRNA silencing of BCL-XL and MCL-1, but not BCL-2, exhibited variable synergy with 5-Azacytidine in vitro. The BCL-XL, BCL-2 and BCL-w inhibitor ABT-737 sensitized most cell lines more potently compared with the selective BCL-2 inhibitor ABT-199, which synergized with 5-Azacytidine mostly at higher doses. Ex vivo, ABT-737 enhanced 5-Azacytidine activity across primary AML, MDS and MPN specimens. Protein levels of BCL-XL, BCL-2 and MCL-1 in 577 AML patient samples showed overlapping expression across AML FAB subtypes and heterogeneous expression within subtypes, further supporting a concept of dual/multiple BCL-2 family member targeting consistent with RNAi and pharmacologic results. Consequently, silencing of MCL-1 and BCL-XL increased the activity of ABT-199. Functional interrogation of BCL-2 family proteins by BH3 profiling performed on patient samples significantly discriminated clinical response versus resistance to 5-Azacytidine-based therapies. On the basis of these results, we propose a clinical trial of navitoclax (clinical-grade ABT-737) combined with 5-Azacytidine in myeloid malignancies, as well as to prospectively validate BH3 profiling in predicting 5-Azacytidine response.

KW - 5-Azacytidine

KW - BH3 profiling

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BCL-2 family proteins as 5-Azacytidine-sensitizing targets and determinants of response in myeloid malignancies

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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