Disruption of pre-B-cell receptor signaling jams the WNT/β-catenin pathway and induces cell death in B-cell acute lymphoblastic leukemia cell lines

Saba, Nakhle S.; Angelova, Magdalena; Lobelle‐Rich, Patricia; Lévy, Laurence

doi:10.1016/j.leukres.2015.08.002

Cited by 12 publications

(14 citation statements)

References 53 publications

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“…This effect was also observed in P493-6 cells, where Tet treatment was able to regulate Che-1 expression ( Fig EV3A). The interference with c-Myc expression was also able to reduce B-ALL cell lines proliferation ( Fig EV3B) and to affect cell viability after 48 h of protein silencing ( Fig EV3C) as previously observed [24][25][26][27]. Next, we analyzed by Western blot c-Myc expression in the same BM samples from pediatric BCP-ALL patients analyzed for Che-1 expression in Fig 1B and C. As shown in Fig 5B, c-Myc was found to be highly expressed in all BCP-ALL samples analyzed as compared to HBMs, where c-Myc expression disappeared.…”

Section: Che-1 Is a C-myc Target Genesupporting

confidence: 84%

Che‐1 is targeted by c‐Myc to sustain proliferation in pre‐B‐cell acute lymphoblastic leukemia

Folgiero

Socolovschi²,

Pallocca³

et al. 2018

EMBO Reports

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Despite progress in treating B-cell precursor acute lymphoblastic leukemia (BCP-ALL), disease recurrence remains the main cause of treatment failure. New strategies to improve therapeutic outcomes are needed, particularly in high-risk relapsed patients. Che-1/AATF (Che-1) is an RNA polymerase II-binding protein involved in proliferation and tumor survival, but its role in hematological malignancies has not been clarified. Here, we show that Che-1 is overexpressed in pediatric BCP-ALL during disease onset and at relapse, and that its depletion inhibits the proliferation of BCP-ALL cells. Furthermore, we report that c-Myc regulates Che-1 expression by direct binding to its promoter and describe a strict correlation between Che-1 expression and c-Myc expression. RNA-seq analyses upon Che-1 or c-Myc depletion reveal a strong overlap of the respective controlled pathways. Genomewide ChIP-seq experiments suggest that Che-1 acts as a downstream effector of c-Myc. These results identify the pivotal role of Che-1 in the control of BCP-ALL proliferation and present the protein as a possible therapeutic target in children with relapsed BCP-ALL.

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Section: Che-1 Is a C-myc Target Genesupporting

confidence: 84%

Che‐1 is targeted by c‐Myc to sustain proliferation in pre‐B‐cell acute lymphoblastic leukemia

Folgiero

Socolovschi²,

Pallocca³

et al. 2018

EMBO Reports

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“…Immunoblot experiments were carried out as previously described (32). Primary antibodies used were anti: MALT1 (cat #2494) and anti-c-PARP (Asp214; cat#9541), t-PARP (cat#9532s), GAPDH (cat#2118S), Bcl-xL (cat#2764S), all from Cell Signaling Technology; CYLD (cat#sc-137139) and Actin (cat#sc-47778), both from Santa Cruz Biotechnology.…”

Section: Methodsmentioning

confidence: 99%

MALT1 Inhibition Is Efficacious in Both Naïve and Ibrutinib-Resistant Chronic Lymphocytic Leukemia

et al. 2017

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The clinical efficacy displayed by ibrutinib in chronic lymphocytic leukemia (CLL) has been challenged by the frequent emergence of resistant clones. The ibrutinib target, Bruton's tyrosine kinase (BTK), is essential for B cell receptor signaling, and most resistant cases carry mutations in BTK or PLCG2, a downstream effector target of BTK. Recent findings show that MI-2, a small molecule inhibitor of the para-caspase MALT1, is effective in preclinical models of another type of BCR pathway-dependent lymphoma. We therefore studied the activity of MI-2 against CLL and ibrutinib-resistant CLL. Treatment of CLL cells in vitro with MI-2 inhibited MALT1 proteolytic activity, reduced BCR and NF-κB signaling, inhibited nuclear translocation of RelB and p50, and decreased Bcl-xL levels. MI-2 selectively induced dose and time-dependent apoptosis in CLL cells, sparing normal B lymphocytes. Furthermore, MI-2 abrogated survival signals provided by stromal cells and BCR cross-linking and was effective against CLL cells harboring features associated with poor outcomes, including 17p deletion and unmutated IGHV. Notably, MI-2 was effective against CLL cells collected from patients harboring mutations conferring resistance to ibrutinib. Overall, our findings provide a preclinical rationale for the clinical development of MALT1 inhibitors in CLL, in particular for ibrutinib-resistant forms of this disease.

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“…These results establish an astoundingly complex contribution of the BCR to MYC‐driven lymphomagenesis and to lymphoma maintenance. A similar role in support of the malignant B‐cell phenotype could be provided by the pre‐BCR in acute lymphoblastic leukemias …”

Section: The Role Of the Bcr In Tumor B‐cell Fitnessmentioning

confidence: 79%

The B‐cell receptor in control of tumor B‐cell fitness: Biology and clinical relevance

Perucho

Tripodo

Sindaco

et al. 2019

Immunological Reviews

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Summary Surface expression of a functional B cell antigen receptor (BCR) is essential for the survival and proliferation of mature B cells. Most types of B‐cell lymphoproliferative disorders retain surface BCR expression, including B‐cell non‐Hodgkin lymphomas (B‐NHL) and chronic lymphocytic leukemia (CLL). Targeting BCR effectors in B‐NHL cell lines in vitro has indicated that this signaling axis is crucial for malignant B cell growth. This has led to the development of inhibitors of BCR signaling, which are currently used for the treatment of CLL and several B‐NHL subtypes. Recent studies based on conditional BCR inactivation in a MYC‐driven mouse B‐cell lymphoma model have revisited the role of the BCR in MYC‐expressing tumor B cells. Indeed, lymphoma cells losing BCR expression continue to grow unless subjected to competition with their BCR‐expressing counterparts, which causes their elimination. Here, we discuss the molecular nature of the fitness signal delivered by the BCR to MYC‐expressing malignant B cells, ensuring their preferential persistence within a rapidly expanding tumor population. We also review growing evidence of Ig‐negative cases belonging to several B‐NHL subtypes and CLL, and discuss the clinical implications of these findings in relation to an emerging picture of clinical resistances to anti‐BCR therapies.

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Disruption of pre-B-cell receptor signaling jams the WNT/β-catenin pathway and induces cell death in B-cell acute lymphoblastic leukemia cell lines

Cited by 12 publications

References 53 publications

Che‐1 is targeted by c‐Myc to sustain proliferation in pre‐B‐cell acute lymphoblastic leukemia

Che‐1 is targeted by c‐Myc to sustain proliferation in pre‐B‐cell acute lymphoblastic leukemia

MALT1 Inhibition Is Efficacious in Both Naïve and Ibrutinib-Resistant Chronic Lymphocytic Leukemia

The B‐cell receptor in control of tumor B‐cell fitness: Biology and clinical relevance

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