Acquisition of the Recurrent Gly101Val Mutation in BCL2 Confers Resistance to Venetoclax in Patients with Progressive Chronic Lymphocytic Leukemia
Open accessPublished version of a preprint
Abstract
The BCL2 inhibitor venetoclax induces high rates of durable remission in patients with previously treated chronic lymphocytic leukemia (CLL). However, despite continuous daily treatment, leukemia recurs in most patients. To investigate the mechanisms of secondary resistance, we analyzed paired pre-venetoclax and progression samples from 15 patients with CLL progression enrolled on venetoclax clinical trials. The novel Gly101Val mutation in BCL2 was identified at progression in 7 patients, but not at study entry. It was first detectable after 19 to 42 months of therapy, and its emergence anticipated clinical disease progression by many months. Gly101Val reduces the affinity of BCL2 for venetoclax by ∼180-fold in surface plasmon resonance assays, thereby preventing the drug from displacing proapoptotic mediators from BCL2 in cells and conferring acquired resistance in cell lines and primary patient cells. This mutation provides new insights into the pathobiology of venetoclax resistance and provides a potential biomarker of impending clinical relapse. Significance: Why CLL recurs in patients who achieve remission with the BCL2 inhibitor venetoclax has been unknown. We provide the first description of an acquired point mutation in BCL2 arising recurrently and exclusively in venetoclax-treated patients. The mutation reduces venetoclax binding and is sufficient to confer resistance. See related commentary by Thangavadivel and Byrd, p. 320. This article is highlighted in the In This Issue feature, p. 305
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Venetoclax is the only BCL2 inhibitor currently approved by the U.S. FDA, but drug resistance driven, in part, by BCL2 mutations, has been reported.
“Venetoclax is the only BCL2 inhibitor currently approved by the U.S. FDA, but drug resistance driven, in part, byBCL2 mutations, has been reported(62).”
From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [62]
The paper’s title, reproduced in our copy’s bibliographic listing, states that a recurrent BCL2 mutation confers resistance to venetoclax in patients with progressive chronic lymphocytic leukemia. The available passages do not address whether venetoclax is the only BCL2 inhibitor approved by the U.S. FDA (searched: FDA approval and BCL2-mutation resistance). (LLM, conf=0.86)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy
Czabotar, P. E., Lessene, G., Strasser, A., & Adams, J. M. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3722 · Cited by 3,219 · see citing works
Self-citationResistance Mechanisms for the Bruton's Tyrosine Kinase Inhibitor Ibrutinib
Woyach, J. A., Furman, R. R., Liu, T.-M., Ozer, H. G., Zapatka, M., Ruppert, A. S., Xue, L., Li, D. H.-H., Steggerda, S. M., Versele, M., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1400029 · Cited by 1,275 · cited 3× · see citing works
“After cessation of venetoclax, a stable proportion of CLL cells bearing Gly101Val persisted for at least 6 months in 5 patients who received BTK inhibitor therapy (Supplementary Fig.”
Leverson, J. D., Phillips, D. C., Mitten, M. J., Boghaert, E. R., Diaz, D., Tahir, S. K., Belmont, L. D., Nimmer, P., Xiao, Y., Ma, X. M., et al. (2015) · Science Translational Medicine · doi:10.1126/scitranslmed.aaa4642 · Cited by 541 · see citing works
Jones, J. A., Mato, A. R., Wierda, W. G., Davids, M. S., Choi, M., Cheson, B. D., Furman, R. R., Lamanna, N., Barr, P. M., Zhou, L., et al. (2018) · The Lancet Oncology · doi:10.1016/s1470-2045(17)30909-9 · Cited by 383 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Mitochondrial Reprogramming Underlies Resistance to BCL-2 Inhibition in Lymphoid Malignancies
Guièze, R., Liu, V. M., Rosebrock, D., Jourdain, A. A., Hernández-Sánchez, M., Martinez Zurita, A., Sun, J., Ten Hacken, E., Baranowski, K., Thompson, P. A., et al. (2019) · Cancer Cell · doi:10.1016/j.ccell.2019.08.005 · Cited by 361 · see citing works
van Bruggen, J. A. C., Martens, A. W. J., Fraietta, J. A., Hofland, T., Tonino, S. H., Eldering, E., Levin, M.-D., Siska, P. J., Endstra, S., Rathmell, J. C., et al. (2019) · Blood · doi:10.1182/blood.2018885863 · Cited by 187 · see citing works
Blombery, P., Thompson, E. R., Lew, T. E., Tiong, I. S., Bennett, R., Cheah, C. Y., Lewis, K. L., Handunnetti, S. M., Tang, C. P. S., Roberts, A., et al. (2022) · Blood Advances · doi:10.1182/bloodadvances.2022008325 · Cited by 91 · see citing works
Self-citationRemoving unwanted variation with CytofRUV to integrate multiple CyTOF datasets
Trussart, M., Teh, C. E., Tan, T., Leong, L., Gray, D. H., & Speed, T. P. (2020) · eLife · doi:10.7554/elife.59630 · Cited by 51 · see citing works
Self-citationHofland, T., de Weerdt, I., ter Burg, H., de Boer, R., Tannheimer, S., Tonino, S. H., Kater, A. P., & Eldering, E. (2019) · The Journal of Immunology · doi:10.4049/jimmunol.1900321 · Cited by 21 · see citing works
Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy
Gruessner, C., Wiestner, A., & Sun, C. (2025) · Leukemia & Lymphoma · doi:10.1080/10428194.2025.2466101 · Cited by 6 · see citing works
“…NR). these results suggest that vene-toclax is effective following cBtKi therapy particularly when used as second or third line treatment [60]. venetoclax is the only Bcl2 inhibitor currently approved by the U.S. FDA, but drug resistance driven, in part, by BCL2 mutations, has been reported [61].”
- Authors
- Blombery, P., Anderson, M. A., Gong, J.-N., Thijssen, R., Birkinshaw, R. W., Thompson, E. R., Teh, C. E., Nguyen, T., Xu, Z., Flensburg, C., Lew, T. E., Majewski, I. J., Gray, D. H. D., Westerman, D. A., Tam, C. S., Seymour, J. F., Czabotar, P. E., Huang, D. C. S., & Roberts, A. W.
- Affiliations
- The Royal Melbourne Hospital (AU)
- 4The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
- The University of Melbourne (AU)
- Walter and Eliza Hall Institute of Medical Research (AU)
- Corresponding author
- Blombery, Piers
- Roberts, Andrew W.
- ORCID
- Venue
- Cancer Discovery
- Published
- 2019-03-01
- Volume
- 9
- Issue
- 3
- Pages
- 342-353
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- OpenAlex
- W2902472954
- Cited by
- 434
- References
- 4
- Citations by year
- 2026: 31 · 2025: 44 · 2024: 56 · 2023: 54 · 2022: 48 · 2021: 70 · 2020: 75 · 2019: 55
- FWCI
- 29.06
- Type
- journal article
- Language
- en
- Open access
- green
- pure.amsterdamumc.nl
- Licence
- other-oa
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- Funders
- Leukemia and Lymphoma Society (5467-18)
- SCOR (7015-18)
- Cancer Council Victoria (1146518, 1102104, 1124178)
- NHMRC (1089072, 1090236, 1079700, 1043149, 1079560, 1141874, 1113133, 1113577)
- Topics
- Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Keywords
- chronic lymphocytic leukemia, venetoclax, acquired drug resistance, relapse
- MeSH terms
- Antineoplastic Agents, Humans, Models, Molecular, Mutation, Neoplasm Recurrence, Local, Protein Conformation, Sulfonamides, Tumor Cells, Cultured, Leukemia, Lymphocytic, Chronic, B-Cell, Drug Resistance, Neoplasm, Bridged Bicyclo Compounds, Heterocyclic, Proto-Oncogene Proteins c-bcl-2, Cell Proliferation, High-Throughput Nucleotide Sequencing
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
