Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia

Tissino, Erika; Benedetti, Dania; Herman, Sarah E. M.; Hacken, Elisa ten; Ahn, Inhye E.; Chaffee, Kari G.; Rossi, Francesca Maria; Bo, Michele Dal; Bulian, Pietro; Bomben, Riccardo; Bayer, Elisabeth; Härzschel, Andrea; Gutjahr, Julia; Postorino, Massimiliano; Santinelli, Enrico; Ayed, Ayed O.; Zaja, Francesco; Chiarenza, Annalisa; Pozzato, Gabriele; Chigaev, Alexandre; Sklar, Larry A.; Burger, Jan A.; Ferrajoli, Alessandra; Shanafelt, Tait D.; Wiestner, Adrian; Poeta, Giovanni Del; Hartmann, Tanja Nicole; Gattei, Valter; Zucchetto, Antonella

doi:10.1084/jem.20171288

Cited by 71 publications

(99 citation statements)

References 56 publications

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“…Given its role in microenvironment interactions, high CD49d expression might be expected to counteract the redistribution effect following administration of BCR pathway inhibitors of leukemic cells from the lymphoid compartment to the peripheral blood [56,[89][90][91][92]. This observation is confirmed by a 2018 study by Tissino et al, demonstrating significantly decreased median % blood absolute lymphocyte count and lymph node mass reduction in CD49d positive cases after treatment with ibrutinib [87]. Furthermore, CD49d positive cases in this study showed independent negative prognostic capability with respect to PFS (HR [95% CI] 3.15 [1.…”

Section: Cd49dmentioning

confidence: 81%

“…CD49d expression, defined by a cutoff of >30% is correlated with poorer survival in cohorts treated both with CIT and ibrutinib [19,87,88]. We recently published data demonstrating equally poor outcomes in the setting of CIT and ibrutinib in CLL patients with bimodal expression of CD49d-characterized by concomitant sub-populations of CD49d pos and CD49d neg clones-compared to homogenous CD49 neg CLL.…”

Section: Cd49dmentioning

confidence: 99%

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An Updated Perspective on Current Prognostic and Predictive Biomarkers in Chronic Lymphocytic Leukemia in the Context of Chemoimmunotherapy and Novel Targeted Therapy

Cohen

Bomben

Pozzo

et al. 2020

Cancers

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Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with a variable clinical course. Novel biomarkers discovered over the past 20 years have revolutionized the way clinicians approach prognostication and treatment especially in the chemotherapy-free era. Herein, we review the best established prognostic and predictive biomarkers in the setting of chemoimmunotherapy (CIT) and novel targeted therapy. We propose that TP53 disruption (defined as either TP53 mutation or chromosome 17p deletion), unmutated immunoglobulin heavy chain variable region gene status (UM IGHV), NOTCH1 mutation, and CD49d expression are the strongest prognosticators of disease progression and overall survival in the field of novel biomarkers including recurrent gene mutations. We also highlight the predictive role of TP53 disruption, UM IGHV, and NOTCH1 mutation in the setting of CIT and TP53 disruption and CD49d expression in the setting of novel targeted therapy employing B-cell receptor (BCR) and B-cell lymphoma-2 (BCL2) inhibition. Finally, we discuss future directions in the field of biomarker development to identify those with relapsed/refractory disease at risk for progression despite treatment with novel therapies.

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Section: Cd49dmentioning

confidence: 81%

Section: Cd49dmentioning

confidence: 99%

An Updated Perspective on Current Prognostic and Predictive Biomarkers in Chronic Lymphocytic Leukemia in the Context of Chemoimmunotherapy and Novel Targeted Therapy

Cohen

Bomben

Pozzo

et al. 2020

Cancers

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“…Prior to each assay, PBMCs were thawed, washed, and allowed to recover for 1 hour at 37 C in complete RPMI1640 medium (supplemented with 10% FBS, 2 mmol/L glutamine, and 1% penicillin/streptomycin). Tumor IGHV usage and mutational status, surface IgM and IgD levels and signaling capacity as measured by intracellular calcium mobilization assay, phenotypic CD38, CD49d, CXCR4 and ZAP70 expression, and FISH characteristics according to D€ ohner classification at baseline were determined as described previously (7,18,28,29).…”

Section: Patients Ibrutinib Treatment and Cell Preparationmentioning

confidence: 99%

“…B-cell receptor (BCR)-associated Bruton tyrosine kinase (BTK) inhibitor ibrutinib has become a milestone for therapeutic success in chronic lymphocytic leukemia (CLL) and has been rapidly shifting patient treatment algorithms away from chemotherapybased regimens (1,2). Inhibition of BTK by ibrutinib affects BCR signaling but also cell adhesion and migration (3)(4)(5), and induces a rapid and prominent lymph node reduction and redistribution of CLL cells into the peripheral blood (2,6,7). The prolonged CLL cell redistribution into the peripheral blood offers a unique way to interpret consequences of continuous separation of CL surface receptors from their ligands in the tissue environment of patients, without need of models in vitro or in animals.…”

Section: Introductionmentioning

confidence: 99%

Ibrutinib Therapy Releases Leukemic Surface IgM from Antigen Drive in Chronic Lymphocytic Leukemia Patients

Drennan

Chiodin

D’Avola

et al. 2019

Clinical Cancer Research

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Purpose: In chronic lymphocytic leukemia (CLL), disease progression associates with surface IgM (sIgM) levels and signaling capacity. These are variably downmodulated in vivo and recover in vitro, suggesting a reversible influence of tissuelocated antigen. Therapeutic targeting of sIgM function via ibrutinib, an inhibitor of Bruton tyrosine kinase (BTK), causes inhibition and tumor cell redistribution into the blood, with significant clinical benefit. Circulating CLL cells persist in an inhibited state, offering a tool to investigate the effects of drug on BTK-inhibited sIgM.Experimental Design: We investigated the consequences of ibrutinib therapy on levels and function of sIgM in circulating leukemic cells of patients with CLL.Results: At week 1, there was a significant increase of sIgM expression (64% increase from pretherapy) on CLL cells either recently released from tissue or persisting in blood. In contrast, surface IgD (sIgD) and a range of other receptors did not change. SIgM levels remained higher than pretherapy in the following 3 months despite gradual cell size reduction and ongoing autophagy and apoptotic activity. Conversely, IgD and other receptors did not increase and gradually declined. Recovered sIgM was fully N-glycosylated, another feature of escape from antigen, and expression did not increase further during culture in vitro. The sIgM was fully capable of mediating phosphorylation of SYK, which lies upstream of BTK in the Bcell receptor pathway.Conclusions: This specific IgM increase in patients underpins the key role of tissue-based engagement with antigen in CLL, confirms the inhibitory action of ibrutinib, and reveals dynamic adaptability of CLL cells to precision monotherapy. Figure 2.Surface expression of receptors on CLL cells during the first 3 months of ibrutinib therapy. PBMCs were taken at pre-, week 1, month 1, or month 3 of ibrutinib therapy and analyzed for cell surface marker expression taking into account CLL cell size. For each marker, the test MFI was divided by FSC 2 . Pretherapy values were normalized to one (white bar). Each bar represents mean with SEM. The statistical significance of difference was analyzed using the Wilcoxon signed rank test of the FSC-adjusted MFI values. Ã , P < 0.05; ÃÃ , P < 0.01; ÃÃÃ , P 0.001. Drennan et al.

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“…In this work, we provided new evidence for BTKi off-target effects that involve downregulation not only of NOTCH1 but also of NOTCH2 activity and JAGGED1 expression. In many tumor subtypes, ibrutinib appears to work via several intracellular signals of cancer growth demonstrating that this drug is not entirely specific in its binding to BTK (39,40). Ibrutinib efficacy was associated to a direct anti-EGFR effect in lung cancer (41) or to the activity against EGFR-induced NF-kB activation in glioma (42).…”

Section: Discussionmentioning

confidence: 99%

Decreased NOTCH1 Activation Correlates with Response to Ibrutinib in Chronic Lymphocytic Leukemia

Papa

Baldoni

Dorillo

et al. 2019

Clinical Cancer Research

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Purpose: Ibrutinib, a Bruton tyrosine kinase inhibitor (BTKi), has improved the outcomes of chronic lymphocytic leukemia (CLL), but primary resistance or relapse are issues of increasing significance. While the predominant mechanism of action of BTKi is the B-cell receptor (BCR) blockade, many offtarget effects are unknown. We investigated potential interactions between BCR pathway and NOTCH1 activity in ibrutinib-treated CLL to identify new mechanisms of therapy resistance and markers to monitor disease response. Experimental Design: NOTCH activations was evaluated either in vitro and ex vivo in CLL samples after ibrutinib treatment by Western blotting. Confocal proximity ligation assay (PLA) experiments and analyses of down-targets of NOTCH1 by qRT-PCR were used to investigate the crosstalk between BTK and NOTCH1. Results: In vitro ibrutinib treatment of CLL significantly reduced activated NOTCH1/2 and induced dephosphory-lation of eIF4E, a NOTCH target in CLL. BCR stimulation increased the expression of activated NOTCH1 that accumulated in the nucleus leading to HES1, DTX1, and c-MYC transcription. Results of in situ PLA experiments revealed the presence of NOTCH1-ICD/BTK complexes, whose number was reduced after ibrutinib treatment. In ibrutinib-treated CLL patients, leukemic cells showed NOTCH1 activity downregulation that deepened over time. The NOTCH1 signaling was restored at relapse and remained activated in ibrutinib-resistant CLL cells. Conclusions: We demonstrated a strong clinical activity of ibrutinib in a real-life context. The ibrutinib clinical efficacy was associated with NOTCH1 activity downregulation that deepened over time. Our data point to NOTCH1 as a new molecular partner in BCR signaling with potential to further improve CLL-targeted treatments.

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Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia

Cited by 71 publications

References 56 publications

An Updated Perspective on Current Prognostic and Predictive Biomarkers in Chronic Lymphocytic Leukemia in the Context of Chemoimmunotherapy and Novel Targeted Therapy

An Updated Perspective on Current Prognostic and Predictive Biomarkers in Chronic Lymphocytic Leukemia in the Context of Chemoimmunotherapy and Novel Targeted Therapy

Ibrutinib Therapy Releases Leukemic Surface IgM from Antigen Drive in Chronic Lymphocytic Leukemia Patients

Decreased NOTCH1 Activation Correlates with Response to Ibrutinib in Chronic Lymphocytic Leukemia

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