Redundant and nonredundant roles for Cdc42 and Rac1 in lymphomas developed in NPM-ALK transgenic mice

Choudhari, Ramesh; Minero, Valerio Giacomo; Menotti, Matteo; Pulito, Roberta; Brakebusch, Cord; Compagno, Mara; Voena, Claudia; Ambrogio, Chiara; Chiarle, Roberto

doi:10.1182/blood-2015-11-683052

Cited by 25 publications

(21 citation statements)

References 28 publications

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“…32,48 More broadly, these findings suggest the importance of TCR signaling as a key pathway involved in lymphomagenesis, 60 as has been demonstrated in mice 61 and is evidenced further by other genes altered by various mechanisms in PTCLs, including rearrangements of SYK, copy number gains of ITK, and point mutations of FYN. 16,49,57,62 These potentially targetable molecular alterations show promise for advances analogous to those resulting from elucidation of dysregulated B-cell receptor signaling in B-cell NHLs.…”

Section: Discussionmentioning

confidence: 53%

“…Because VAV1 GEF activity predominantly targets the Rho family GTPase RAC1 (and to a lesser extent RHOA and CDC42), 30,31 and RAC1 has been demonstrated to promote migration in an ALCL model, 32 we measured Rac activation following VAV1-GSS transfection in Jurkat cells. VAV1-GSS overexpression increased active Rac (GTP-Rac; 173% of control; P 5 .054; Figure 4A-B).…”

Section: Vav1-gss Drives Growth Through Rac1 and Can Be Targeted By Rmentioning

confidence: 99%

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Integrated mate-pair and RNA sequencing identifies novel, targetable gene fusions in peripheral T-cell lymphoma

Boddicker¹,

Razidlo

Dasari

et al. 2016

Blood

100

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Peripheral T-cell lymphomas (PTCLs) represent a heterogeneous group of T-cell malignancies that generally demonstrate aggressive clinical behavior, often are refractory to standard therapy, and remain significantly understudied. The most common World Health Organization subtype is PTCL, not otherwise specified (NOS), essentially a “wastebasket” category because of inadequate understanding to assign cases to a more specific diagnostic entity. Identification of novel fusion genes has contributed significantly to improving the classification, biologic understanding, and therapeutic targeting of PTCLs. Here, we integrated mate-pair DNA and RNA next-generation sequencing to identify chromosomal rearrangements encoding expressed fusion transcripts in PTCL, NOS. Two of 11 cases had novel fusions involving VAV1, encoding a truncated form of the VAV1 guanine nucleotide exchange factor important in T-cell receptor signaling. Fluorescence in situ hybridization studies identified VAV1 rearrangements in 10 of 148 PTCLs (7%). These were observed exclusively in PTCL, NOS (11%) and anaplastic large cell lymphoma (11%). In vitro, ectopic expression of a VAV1 fusion promoted cell growth and migration in a RAC1-dependent manner. This growth was inhibited by azathioprine, a clinically available RAC1 inhibitor. We also identified novel kinase gene fusions, ITK-FER and IKZF2-ERBB4, as candidate therapeutic targets that show similarities to known recurrent oncogenic ITK-SYK fusions and ERBB4 transcript variants in PTCLs, respectively. Additional novel and potentially clinically relevant fusions also were discovered. Together, these findings identify VAV1 fusions as recurrent and targetable events in PTCLs and highlight the potential for clinical sequencing to guide individualized therapy approaches for this group of aggressive malignancies.

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Section: Discussionmentioning

confidence: 53%

Section: Vav1-gss Drives Growth Through Rac1 and Can Be Targeted By Rmentioning

confidence: 99%

Integrated mate-pair and RNA sequencing identifies novel, targetable gene fusions in peripheral T-cell lymphoma

Boddicker¹,

Razidlo

Dasari

et al. 2016

Blood

100

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“…Early studies showed that treatment with NSC23766, a chemical inhibitor of Rac1, blocked the invasion and metastasis phenotype in multiple cancer cells 42 . It has also been shown that inhibition of Rac1 signaling in a murine lymphoma model abrogated tumor progression and metastasis in vivo 43 . This evidence demonstrated that Rac1 could be regarded as a therapeutic target for anticancer drugs.…”

Section: Discussionmentioning

confidence: 99%

Prognostic and Clinicopathological Value of Rac1 in Cancer Survival: Evidence from a Meta-Analysis

et al. 2018

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Purpose: The role of Rac1 in cancer survival has been widely studied. However, the prognostic and clinicopathological value of Rac1 remains inconclusive. We performed a meta-analysis to clarify the role of Rac1 in cancer survival as well as its association with clinicopathological features.Methods: Eligible studies were searched from PubMed, Cochrane Library, Embase, and Web of Science databases. The pooled hazard ratios (HRs) and odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were used to detect the prognostic and clinicopathological role of Rac1.Results: A total of 14 studies including 1793 patients were enrolled in the present meta-analysis. Pooled HR for overall survival (OS) (HR=2.02, 95% CI: 1.70-2.39) and disease-free survival (DFS) (HR=2.64, 95% CI: 1.71-4.09) indicated a significant poor prognostic effect for Rac1. Positive Rac1 expression was found to be correlated with tumor stage, blood vessel invasion, and lymph metastasis, but not with histological differentiation. Sensitivity test showed no single study altered OS or DFS significantly. No publication bias was detected by Egger's test and Begg's funnel plot test.Conclusion: This meta-analysis indicated that Rac1 could be used as a potential marker to predict cancer prognosis. Additionally, Rac1 expression was associated with the malignancy-related phenotype.

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“…Moreover, ALK fusion-mediated activation of STAT3 has been shown to be required for the maintenance of the transformed phenotype in ALK + ALCL (Chiarle et al 2005). ALK fusions constitutively activate VAV1 and VAV3 in ALCL, increasing RAC1 and CDC42 activity, down-regulating the Wiskott-Aldrich syndrome protein (WASP) and WASP-interacting protein (WIP) tumor suppressors and promoting lymphoma survival (Choudhari et al 2016;Menotti et al 2019).…”

Section: Anaplastic Large-cell Lymphomasmentioning

confidence: 99%

Biology and Molecular Pathogenesis of Mature T-Cell Lymphomas

Cortés

Palomero

2020

Cold Spring Harb Perspect Med

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Redundant and nonredundant roles for Cdc42 and Rac1 in lymphomas developed in NPM-ALK transgenic mice

Abstract: Key Points Rac1 and Cdc42 possess nonredundant roles in preventing apoptosis of NPM-ALK lymphoma cells. Simultaneous deletions of both Rac1 and Cdc42 prevents NPM-ALK lymphoma dissemination in vivo.

Cited by 25 publications

References 28 publications

Integrated mate-pair and RNA sequencing identifies novel, targetable gene fusions in peripheral T-cell lymphoma

Integrated mate-pair and RNA sequencing identifies novel, targetable gene fusions in peripheral T-cell lymphoma

Prognostic and Clinicopathological Value of Rac1 in Cancer Survival: Evidence from a Meta-Analysis

Biology and Molecular Pathogenesis of Mature T-Cell Lymphomas

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