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BCL-2 dependence is a favorable predictive marker of response to therapy for chronic lymphocytic leukemia
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Chong, Stephen Jun Fei
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Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA
Natl Univ Singapore NUS, NUS Ctr Canc Res N2CR, Dept Physiol, Singapore, Singapore
NUS, Canc Sci Inst Singapore, N2CR, Singapore, Singapore Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA

Lu, Junyan
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Heidelberg Univ, Med Fac Heidelberg, Heidelberg, Germany Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA

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Lehmberg, Timothy Z.
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Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA

Eu, Jie Qing
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NUS, Canc Sci Inst Singapore, N2CR, Singapore, Singapore Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA

Wang, Jing
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Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA

Zhu, Fen
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Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA

Kong, Li Ren
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NUS, Canc Sci Inst Singapore, N2CR, Singapore, Singapore Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA

Fernandes, Stacey M.
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Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA

Zhang, Jeremy
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Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA

Herbaux, Charles
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Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA

Goh, Boon Cher
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NUS, Canc Sci Inst Singapore, N2CR, Singapore, Singapore Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA

Brown, Jennifer R.
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Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA

Niemann, Carsten U.
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Dept Hematol, Rigshosp, Copenhagen, Denmark Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA

Huber, Wolfgang
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European Mol Biol Lab, Heidelberg, Germany Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA

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Davids, Matthew S.
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Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA
机构:
[1] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA
[2] Natl Univ Singapore NUS, NUS Ctr Canc Res N2CR, Dept Physiol, Singapore, Singapore
[3] Heidelberg Univ, Med Fac Heidelberg, Heidelberg, Germany
[4] Dept Hematol, Rigshosp, Copenhagen, Denmark
[5] NUS, Canc Sci Inst Singapore, N2CR, Singapore, Singapore
[6] European Mol Biol Lab, Heidelberg, Germany
[7] Univ Zurich, Dept Med Oncol & Hematol, Zurich, Switzerland
[8] Univ Hosp Zurich, Zurich, Switzerland
关键词:
NF-KAPPA-B;
DNA-DAMAGE;
APOPTOSIS;
MUTATIONS;
PHOSPHORYLATION;
VENETOCLAX;
EXPRESSION;
RESISTANCE;
CELLS;
NOXA;
D O I:
10.1186/s12943-025-02260-7
中图分类号:
Q5 [生物化学];
Q7 [分子生物学];
学科分类号:
071010 ;
081704 ;
摘要:
BackgroundEstablished genetic biomarkers in chronic lymphocytic leukemia (CLL) have been useful in predicting response to chemoimmunotherapy but are less predictive of response to targeted therapies. With several such targeted therapies now approved for CLL, identifying novel, non-genetic predictive biomarkers of response may help to select the optimal therapy for individual patients.MethodsWe coupled data from a functional precision medicine technique called BH3-profiling, which assesses cellular cytochrome c loss levels as indicators for survival dependence on anti-apoptotic proteins, with multi-omics data consisting of targeted and whole-exome sequencing, genome-wide DNA methylation profiles, RNA-sequencing, protein and functional analyses, to identify biomarkers for treatment response in CLL patients.ResultsWe initially studied 73 CLL patients from a discovery cohort. We found that greater dependence on the anti-apoptotic BCL-2 protein was associated with prognostically favorable genetic biomarkers. Furthermore, BCL-2 dependence was strongly associated with gene expression patterns and signaling pathways that suggest a more targeted drug-sensitive milieu and was predictive of drug responses. We subsequently demonstrated that these associations were causal in cell lines and additional CLL patient samples. To validate the findings from our discovery cohort and in vitro studies, we utilized primary CLL cells from 54 additional patients treated on a prospective, phase-2 clinical trial of the BTK inhibitor ibrutinib given in combination with chemoimmunotherapy (fludarabine, cyclophosphamide, rituximab) and confirmed in this independent dataset that higher BCL-2 dependence predicted favorable clinical response, independent of the genetic background of the CLL cells.ConclusionWe comprehensively defined BCL-2 dependence as a potential functional and predictive biomarker of treatment response in CLL, underscoring the importance of characterizing apoptotic signaling in CLL to stratify patients beyond genetic markers and identifying novel combinations to exploit BCL-2 dependence therapeutically. Our approach has the potential to help optimize targeted therapy combinations for CLL patients.
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