c-Abl kinase inhibitors overcome CD40-mediated drug resistance in CLL: implications for therapeutic targeting of chemoresistant niches

Hallaert, Delfine Y.H.; Jaspers, Annelieke; Noesel, Carel J. van; Oers, Marinus H. J. van; Kater, Arnon P.; Eldering, Eric

doi:10.1182/blood-2008-03-146704

Cited by 108 publications

(158 citation statements)

References 57 publications

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“…In agreement with our previous studies, 5,6 CD40-stimulated CLL cells were resistant to fludarabine, roscovitine and bortezomib ( Figure 1d). CD40-stimulated CLL cells with unmutated and mutated immunoglobulin variable heavy-chain (IGHV) genes had similar sensitivity to rituximab-mediated death (data not shown), and no differences in rituximab-induced cell death was observed between never treated and previously treated patients.…”

Section: Cd40 Stimulation Sensitizes Cll Cells To Anti-cd20-mediated supporting

confidence: 93%

“…By bypassing the anti-apoptotic machinery, 6,7,17 RXL is able to induce caspase-independent cell death in CD40-stimulated CLL cells that are resistant to various drugs as result of upregulation of Bcl-2 family members. 5,6 Moreover, our findings suggest that it might be very relevant to combine rituximab with other ROS-inducing drugs like arsenic trioxide 56 or cisplatin. 59 …”

Section: Discussionmentioning

confidence: 78%

“…(1) Although CD40 stimulation renders CLL cells resistant to various cytotoxic drugs, 5,6 it sensitizes CLL cells to anti-CD20-mediated cell death, also in p53 dysfunctional CLL cells. (2) This increased sensitivity cannot be explained by a change in CD20 expression levels and appears not to be a feature of all mAbmediated cell death, as it is not observed with anti-CD52 treatment.…”

Section: Discussionmentioning

confidence: 99%

“…5,6,25 But the sensitivity of CD40-stimulated CLL cells to CD20 antibodies is not known. Therefore, rituximab-mediated cell death of CD40-stimulated CLL cells from 17 CLL patients was tested.…”

Section: Cd40 Stimulation Sensitizes Cll Cells To Anti-cd20-mediated mentioning

confidence: 99%

“…2,4 We have previously shown that in vitro CD40 stimulation of peripheral bloodderived CLL cells can to a certain extent mimic the lymph node micro-environment and result in resistance to cytotoxic drugs. [5][6][7] Recently, it has been shown in a large randomized phase III trial that addition of the chimeric anti-CD20 monoclonal antibody (mAb) rituximab (R) to fludarabine and cyclophosphamide improves both progression free survival and overall survival in p53 functional, previously untreated CLL patients. 8 This is remarkable in view of the relatively low efficacy of rituximab when used as monotherapy at dosages used in the treatment of lymphoma.…”

Section: Introductionmentioning

confidence: 99%

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CD40 stimulation sensitizes CLL cells to rituximab-induced cell death

et al. 2011

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In vitro CD40-stimulated chronic lymphocytic leukemia (CLL) cells are resistant to cytotoxic drugs. In sharp contrast, we here show that CD40 stimulation sensitizes CLL cells to rituximabmediated cell death. This increased sensitivity is specific for anti-CD20 treatment. Rituximab-mediated death in CD40-stimulated CLL cells shows rapid kinetics (within hours), and is caspase and p53 independent, but depends on extracellular Ca 2 þ and reactive oxygen species (ROS) production. By increasing basal ROS production, CD40 stimulation sensitizes CLL cells to rituximab-mediated death. Our findings provide a rationale for combination treatment of CLL with cytotoxic drugs and anti-CD20 monoclonal antibodies.

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Section: Cd40 Stimulation Sensitizes Cll Cells To Anti-cd20-mediated supporting

confidence: 93%

Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Section: Cd40 Stimulation Sensitizes Cll Cells To Anti-cd20-mediated mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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CD40 stimulation sensitizes CLL cells to rituximab-induced cell death

et al. 2011

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JAK–STAT signalling shapes the NF‐κB response in CLL towards venetoclax sensitivity or resistance via Bcl‐XL

et al. 2023

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Preventing or overcoming resistance to the Bcl-2 inhibitor venetoclax is an emerging unmet cl i ni cal need in patients with chronic lymphocytic leukemia (CLL). The upregulation of anti -apoptoti c Bcl-2 members through signaling pathways within the tumor microenvironment appears as a major factor leading to resistance to venetoclax. Previously, we reported that T cells can drive resistance through CD40 and non-canonical NF-κB activation and subsequent Bcl-XL induction. Moreover, the T cellderived cytokines IL-21 and IL-4 differentially affect Bcl-XL expression and sensitivity to venetoclax via unknown mechanisms. Here, we mechanistically dissected how Bcl-XL is regulated in the conte xt of JAK-STAT signaling in primary CLL. First, we demonstrated a clear antagonistic role of IL-21/STAT3 signaling in the NF-κB-mediated expression of Bcl-XL, whereas IL-4/STAT6 further promoted the expression of Bcl-XL. In comparison, Bfl-1, another NF-κB target, was not differentially affected by either cytokine. Second, STAT3 and STAT6 affected Bcl-XL transcription by binding to its promoter without disrupting the DNA-binding activity of NF-κB. Third, in situ proximity ligation assays (i sPLAs) indicated crosstalk between JAK-STAT signaling and NF-κB, in which STAT3 inhibited canonical NF-κB by accelerating nuclear export, and STAT6 promoted non-canonical NF-κB. Finally, NF-κB inducing kinase (NIK) inhibition interrupted the NF-κB/STAT crosstalk and re-sensitized CLL cells to venetoclax.In conclusion, we uncovered distinct crosstalk mechanisms that shape the NF-κB response in CLL towards venetoclax sensitivity or resistance via Bcl-XL, thereby revealing new potential therapeutic targets.

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Obinutuzumab (Gazyva®), a Novel Glycoengineered Type II CD20 Antibody for the Treatment of Chronic Lymphocytic Leukemia and Non‐Hodgkin's Lymphoma

Klein

Bacac

Umaña

et al. 2014

Handbook of Therapeutic Antibodies

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c-Abl kinase inhibitors overcome CD40-mediated drug resistance in CLL: implications for therapeutic targeting of chemoresistant niches

Abstract: In lymph node (LN) proliferation centers in chronic lymphocytic leukemia (CLL), the environment protects from apoptotic and cytotoxic triggers. Here, we aimed to define the molecular basis for the in-

Cited by 108 publications

References 57 publications

CD40 stimulation sensitizes CLL cells to rituximab-induced cell death

CD40 stimulation sensitizes CLL cells to rituximab-induced cell death

JAK–STAT signalling shapes the NF‐κB response in CLL towards venetoclax sensitivity or resistance via Bcl‐XL

Obinutuzumab (Gazyva®), a Novel Glycoengineered Type II CD20 Antibody for the Treatment of Chronic Lymphocytic Leukemia and Non‐Hodgkin's Lymphoma

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