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HCK is a survival determinant transactivated by mutated MYD88, and a direct target of ibrutinib
Open accessAbstract
Activating mutations in MYD88 are present in ∼95% of patients with Waldenström macroglobulinemia (WM), as well as other B-cell malignancies including activated B-cell (ABC) diffuse large B-cell lymphoma (DLBCL). In WM, mutated MYD88 triggers activation of Bruton tyrosine kinase (BTK). Ibrutinib, a pleiotropic kinase inhibitor that targets BTK, is highly active in patients with mutated MYD88. We observed that mutated MYD88 WM and ABC DLBCL cell lines, as well as primary WM cells show enhanced hematopoietic cell kinase (HCK) transcription and activation, and that HCK is activated by interleukin 6 (IL-6). Over-expression of mutated MYD88 triggers HCK and IL-6 transcription, whereas knockdown of HCK reduced survival and attenuated BTK, phosphoinositide 3-kinase/AKT, and mitogen-activated protein kinase/extracellular signal-regulated kinase signaling in mutated MYD88 WM and/or ABC DLBCL cells. Ibrutinib and the more potent HCK inhibitor A419259, blocked HCK activation and induced apoptosis in mutated MYD88 WM and ABC DLBCL cells. Docking and pull-down studies confirmed that HCK was a target of ibrutinib. Ibrutinib and A419259 also blocked adenosine triphosphate binding to HCK, whereas transduction of mutated MYD88 expressing WM cells with a mutated HCK gatekeeper greatly increased the half maximal effective concentration for ibrutinib and A419259. The findings support that HCK expression and activation is triggered by mutated MYD88, supports the growth and survival of mutated MYD88 WM and ABC DLBCL cells, and is a direct target of ibrutinib. HCK represents a novel target for therapeutic development in MYD88-mutated WM and ABC DLBCL, and possibly other diseases driven by mutated MYD88.
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“Consistent with the activity of ibrutinib on other TEC family kinases, its activity against HCK (in addition to BTK) is responsible for antiproliferative effects in L265P-MYD88-driven ABC DLBCL cells. 37”
From Bruton tyrosine kinase degradation as a therapeutic strategy for cancer (2019) · cites this paper as [37]
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“the HCK inhibitor A419259 37 exhibited strong synergy with both DD-03-007 and DD-03-171 in TMD8 cells at numerous doses (Figure 3C).”
From Bruton tyrosine kinase degradation as a therapeutic strategy for cancer (2019) · cites this paper as [37]
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MYD88 L265P Somatic Mutation in Waldenström's Macroglobulinemia
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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 1×
“It also remains possible that mutations in the gatekeeper site of HCK could contribute to ibrutinib resistance, akin to that observed with BTK mutations in chronic lymphocytic leukemia patients, and warrant examination.(40) Finally, the potential to developmore potent HCK inhibitors is suggested by these findings.”
ResultTargeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma
Wilson, W. H., Young, R. M., Schmitz, R., Yang, Y., Pittaluga, S., Wright, G. W., Lih, C., Williams, P. M., Shaffer, A. L., Gerecitano, J. F., et al. (2015) · Nature Medicine · doi:10.1038/nm.3884 · Cited by 1,155
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“5 nM) and well within the pharmacologically achievable levels of ibrutinib.(10,39) We provide definitive evidence in this report that HCK is a target of ibrutinib using docking models, direct pull-down experiments with biotinylated ibrutinib, cellular target engagement, and cellular rescue with inhibitor-resistant mut…”
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Self-citationIbrutinib Monotherapy in Symptomatic, Treatment-Naïve Patients With Waldenström Macroglobulinemia
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Metadata
- Authors
- Yang, G., Buhrlage, S. J., Tan, L., Liu, X., Chen, J., Xu, L., Tsakmaklis, N., Chen, J. G., Patterson, C. J., Brown, J. R., Castillo, J. J., Zhang, W., Zhang, X., Liu, S., Cohen, P., Hunter, Z. R., Gray, N., & Treon, S. P.
- Affiliations
- Harvard University (US)
- University of Massachusetts Boston (US)
- University of Dundee (GB)
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2016-06-23
- Volume
- 127
- Issue
- 25
- Pages
- 3237-3252
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2347186599
- Cited by
- 135
- References
- 44
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 13 · 2023: 10 · 2022: 14 · 2021: 22 · 2020: 19 · 2019: 11 · 2018: 16 · 2017: 9 · 2016: 4
- FWCI
- 9.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion, other-oa)
- Funders
- Leukemia and Lymphoma Society
- Medical Research Council (MR/K000985/1)
- Topics
- Health Sciences › Medicine › Hematology › Chronic Lymphocytic Leukemia Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
- Keywords
- hematopoietic cell kinase, MYD88 mutation, Waldenström macroglobulinemia, ibrutinib, Bruton's tyrosine kinase, interleukin-6, cell survival, apoptosis, PI3K/Akt signaling, ERK signaling, drug resistance
- MeSH terms
- Adenine, Antineoplastic Agents, Cell Survival, Humans, Waldenstrom Macroglobulinemia, Piperidines, Pyrazoles, Pyrimidines, Transcriptional Activation, Interleukin-6, Gene Expression Regulation, Leukemic, Lymphoma, Large B-Cell, Diffuse, Cell Line, Tumor, Mutant Proteins, Proto-Oncogene Proteins c-hck, Myeloid Differentiation Factor 88, Molecular Targeted Therapy
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