TY - JOUR
T1 - Ibrutinib sensitizes CLL cells to venetoclax by interrupting TLR9-induced CD40 upregulation and protein translation
AU - Kielbassa, Karoline
AU - Haselager, Marco V.
AU - Bax, Danique J. C.
AU - van Driel, Bianca F.
AU - Dubois, Julie
AU - Levin, Mark-David
AU - Kersting, Sabina
AU - Svanberg, Rebecka
AU - Niemann, Carsten U.
AU - Kater, Arnon P.
AU - Eldering, Eric
N1 - Funding Information: KK is financed by the PPP Allowance made available by Top Sector Life Sciences & Health to Samenwerkende Gezondheidsfondsen (SGF) under projectnumber LSHM18055-SGF to stimulate public-private partnerships and co-financing by health foundations that are part of the SFG. For more information: www.target-to-b.nl. MVH was funded by the Blaauboer Fund via the AMC Foundation. Samples were obtained from biobanked material of the Hovon 141/Vision clinical trial. The trial is sponsored by the non-profit study organization HOVON and designed by the investigators. The trial is financially supported by AbbVie and Janssen. We thank Lori D. Parisi for critical reading and suggestions for this manuscript. We thank master student Jasper Geissler for his contribution to the data in Fig. 4. Funding Information: KK is financed by the PPP Allowance made available by Top Sector Life Sciences & Health to Samenwerkende Gezondheidsfondsen (SGF) under projectnumber LSHM18055-SGF to stimulate public-private partnerships and co-financing by health foundations that are part of the SFG. For more information: www.target-to-b.nl . MVH was funded by the Blaauboer Fund via the AMC Foundation. Samples were obtained from biobanked material of the Hovon 141/Vision clinical trial. The trial is sponsored by the non-profit study organization HOVON and designed by the investigators. The trial is financially supported by AbbVie and Janssen. We thank Lori D. Parisi for critical reading and suggestions for this manuscript. We thank master student Jasper Geissler for his contribution to the data in Fig. . Publisher Copyright: © 2023, The Author(s).
PY - 2023/6
Y1 - 2023/6
N2 - Chronic lymphocytic leukemia (CLL) cells upregulate Bcl-2 proteins within the lymph node (LN) microenvironment. Signaling via B-cell receptor, Toll-like receptors and CD40 collectively reduce sensitivity to the BCL-2 inhibitor venetoclax. Time-limited treatment with venetoclax plus the BTK-inhibitor ibrutinib results in deep remissions, but how this combination affects LN-related signaling is not yet completely clear. Therefore, samples obtained from the HOVON141/VISION phase 2 clinical trial were used to analyze this. Two cycles of lead-in ibrutinib monotherapy resulted in decreased protein expression of Bcl-2 proteins in circulating CLL cells. Strikingly, at this timepoint CD40-induced venetoclax resistance was strongly attenuated, as was expression of CD40. Since CD40 signaling occurs within the CLL LN, we tested various LN-related signals that could affect CD40 signaling. While BCR stimulation had only a minor effect, TLR9 stimulation via CpG led to significantly increased CD40 expression and importantly, reverted the effects of ibrutinib treatment on venetoclax sensitivity by inducing overall protein translation. Together, these findings identify a novel effect of ibrutinib: interruption of TLR9-induced CD40 upregulation and translation of pro-survival proteins. This mechanism may potentially further inhibit priming of CLL cells in the LN microenvironment for venetoclax resistance.
AB - Chronic lymphocytic leukemia (CLL) cells upregulate Bcl-2 proteins within the lymph node (LN) microenvironment. Signaling via B-cell receptor, Toll-like receptors and CD40 collectively reduce sensitivity to the BCL-2 inhibitor venetoclax. Time-limited treatment with venetoclax plus the BTK-inhibitor ibrutinib results in deep remissions, but how this combination affects LN-related signaling is not yet completely clear. Therefore, samples obtained from the HOVON141/VISION phase 2 clinical trial were used to analyze this. Two cycles of lead-in ibrutinib monotherapy resulted in decreased protein expression of Bcl-2 proteins in circulating CLL cells. Strikingly, at this timepoint CD40-induced venetoclax resistance was strongly attenuated, as was expression of CD40. Since CD40 signaling occurs within the CLL LN, we tested various LN-related signals that could affect CD40 signaling. While BCR stimulation had only a minor effect, TLR9 stimulation via CpG led to significantly increased CD40 expression and importantly, reverted the effects of ibrutinib treatment on venetoclax sensitivity by inducing overall protein translation. Together, these findings identify a novel effect of ibrutinib: interruption of TLR9-induced CD40 upregulation and translation of pro-survival proteins. This mechanism may potentially further inhibit priming of CLL cells in the LN microenvironment for venetoclax resistance.
UR - http://www.scopus.com/inward/record.url?scp=85153616299&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41375-023-01898-w
DO - https://doi.org/10.1038/s41375-023-01898-w
M3 - Article
C2 - 37100883
SN - 0887-6924
VL - 37
SP - 1268
EP - 1276
JO - Leukemia
JF - Leukemia
IS - 6
ER -