The DOI matches its Crossref record; 8 of the 8 references it cites were found in a registry or an index.
5-Azacitidine Induces NOXA to Prime AML Cells for Venetoclax-Mediated Apoptosis
Abstract
Purpose: Patients with acute myeloid leukemia (AML) frequently do not respond to conventional therapies. Leukemic cell survival and treatment resistance have been attributed to the overexpression of B-cell lymphoma 2 (BCL-2) and aberrant DNA hypermethylation. In a phase Ib study in elderly patients with AML, combining the BCL-2 selective inhibitor venetoclax with hypomethylating agents 5-azacitidine (5-Aza) or decitabine resulted in 67% overall response rate; however, the underlying mechanism for this activity is unknown. Experimental Design: We studied the consequences of combining two therapeutic agents, venetoclax and 5-Aza, in AML preclinical models and primary patient samples. We measured expression changes in the integrated stress response (ISR) and the BCL-2 family by Western blot and qPCR. Subsequently, we engineered PMAIP1 (NOXA)- and BBC3 (PUMA)-deficient AML cell lines using CRISPR-Cas9 methods to understand their respective roles in driving the venetoclax/5-Aza combinatorial activity. Results: In this study, we demonstrate that venetoclax and 5-Aza act synergistically to kill AML cells in vitro and display combinatorial antitumor activity in vivo. We uncover a novel nonepigenetic mechanism for 5-Aza–induced apoptosis in AML cells through transcriptional induction of the proapoptotic BH3-only protein NOXA. This induction occurred within hours of treatment and was mediated by the ISR pathway. NOXA was detected in complex with antiapoptotic proteins, suggesting that 5-Aza may be “priming” the AML cells for venetoclax-induced apoptosis. PMAIP1 knockout confirmed its major role in driving venetoclax and 5-Aza synergy. Conclusions: These data provide a novel nonepigenetic mechanism of action for 5-Aza and its combinatorial activity with venetoclax through the ISR-mediated induction of PMAIP1.
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The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity
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“Hypomethylating agents (HMAs), such as the cytidine analogs 5-azacitidine (5-Aza) and decitabine, demonstrate single-agent activity in 25% to 50% of patients with myelodysplastic syndrome (MDS; ref.”
BackgroundNoxa, a BH3-Only Member of the Bcl-2 Family and Candidate Mediator of p53-Induced Apoptosis
Oda, E., Ohki, R., Murasawa, H., Nemoto, J., Shibue, T., Yamashita, T., Tokino, T., Taniguchi, T., & Tanaka, †. N. (2000) · Science · doi:10.1126/science.288.5468.1053 · Cited by 2,112
BCL-2 family proteins: changing partners in the dance towards death
Kale, J., Osterlund, E. J., & Andrews, D. W. (2018) · Cell Death & Differentiation · doi:10.1038/cdd.2017.186 · Cited by 1,574
p53- and Drug-Induced Apoptotic Responses Mediated by BH3-Only Proteins Puma and Noxa
Villunger, A., Michalak, E. M., Coultas, L., Müllauer, F., Böck, G., Ausserlechner, M. J., Adams, J. M., & Strasser, A. (2003) · Science · doi:10.1126/science.1090072 · Cited by 1,327
Venetoclax-Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia
Seymour, J. F., Kipps, T. J., Eichhorst, B., Hillmen, P., D’Rozario, J., Assouline, S., Owen, C., Gerecitano, J., Robak, T., De la Serna, J., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1713976 · Cited by 940
Pollyea, D. A., Stevens, B. M., Jones, C. L., Winters, A., Pei, S., Minhajuddin, M., D’Alessandro, A., Culp-Hill, R., Riemondy, K. A., Gillen, A. E., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0233-1 · Cited by 778
Inhibition of Amino Acid Metabolism Selectively Targets Human Leukemia Stem Cells
Jones, C. L., Stevens, B. M., D'Alessandro, A., Reisz, J. A., Culp-Hill, R., Nemkov, T., Pei, S., Khan, N., Adane, B., Ye, H., et al. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.10.005 · Cited by 585
Cited by
Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia
DiNardo, C. D., Jonas, B. A., Pullarkat, V., Thirman, M. J., Garcia, J. S., Wei, A. H., Konopleva, M., Döhner, H., Letai, A., Fenaux, P., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa2012971 · Cited by 2,900
The BCL2 family: from apoptosis mechanisms to new advances in targeted therapy
Vogler, M., Braun, Y., Smith, V. M., Westhoff, M.-A., Pereira, R. S., Pieper, N. M., Anders, M., Callens, M., Vervliet, T., Abbas, M., et al. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02176-0 · Cited by 462
BH3 Mimetics in Hematologic Malignancies
Klener, P., Sovilj, D., Renesova, N., & Andera, L. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms221810157 · Cited by 31
Metadata
- Authors
- Jin, S., Cojocari, D., Purkal, J. J., Popovic, R., Talaty, N. N., Xiao, Y., Solomon, L. R., Boghaert, E. R., Leverson, J. D., & Phillips, D. C.
- Venue
- Clinical Cancer Research
- Published
- 2020-07-01
- Volume
- 26
- Issue
- 13
- Pages
- 3371-3383
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W3006513842
- Cited by
- 194
- References
- 8
- FWCI
- 12.69
- Type
- journal article
- Language
- en
- Open access
- closed
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- Jin, S., Cojocari, D., Purkal, J. J., Popovic, R., Talaty, N. N., Xiao, Y., Solomon, L. R., Boghaert, E. R., Leverson, J. D., & Phillips, D. C. (2020). 5-Azacitidine Induces NOXA to Prime AML Cells for Venetoclax-Mediated Apoptosis. Clinical Cancer Research. https://doi.org/10.1158/1078-0432.ccr-19-1900
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