Publications by authors named "Patricia Gomez-Bougie"

The CRCINA inaugural symposium, a meeting on tumor and immune ecosystems, took place in the vibrant and picturesque city of Nantes. The meeting gathered world-renowned experts in cancer biology and immunology. It showcased the most advanced science on mechanisms driving cellular heterogeneity, plasticity, and signaling in normal and cancer cellular ecosystems, which contribute to cancer development, progression, and therapeutic resistance.

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In multiple myeloma, as in B-cell malignancies, mono- and especially bi-allelic gene inactivation is a high-risk factor for treatment resistance, and there are currently no therapies specifically targeting p53 deficiency. In this study, we evaluated if the loss of cell cycle control in p53-deficient myeloma cells would confer a metabolically actionable vulnerability. We show that CTP synthase 1 (), which encodes a CTP synthesis rate-limiting enzyme essential for DNA and RNA synthesis in lymphoid cells, is overexpressed in samples from myeloma patients displaying a high proliferation rate (high expression) or a low p53 score (synonymous with deletion and/or mutation).

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Article Synopsis
  • Researchers used CRISPR/Cas9 to create TP53-/- clones from human myeloma cell lines to study p53-dependent gene expression, identifying a functional score based on 13 genes downregulated when p53 is silenced.
  • This score can differentiate myeloma cells based on TP53 status, predict patient survival, and identifies patients with complete TP53 inactivation.
  • The study found that the p53-regulated gene BAX impacts myeloma cell sensitivity to specific treatments, and combining MCL1 and BCL2 inhibitors may provide better treatment options for patients with TP53 inactivation.
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Secondary plasma cell leukemia (sPCL) is a rare form of aggressive plasma cell malignancy arising mostly at end-stage refractory multiple myeloma and consequently presenting limited therapeutic options. We analyzed 13 sPCL for their sensitivity to BH3 mimetics targeting either BCL2 (venetoclax) or BCLXL (A1155463) and showed that 3 sPCL were efficiently killed by venetoclax and 3 sPCL by A1155463. Accordingly, BH3 profiling of 2 sPCL sensitive to BCLXL inhibition confirmed their high BCLXL primed profile.

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Multiple myeloma is a plasma cell malignancy that escapes from apoptosis by heterogeneously over-expressing anti-apoptotic BCL2 proteins. Myeloma cells with a t(11;14) translocation present a particular vulnerability to BCL2 inhibition while a majority of myeloma cells relies on MCL1 for survival. The present study aimed to determine whether the combination of BCL2 and MCL1 inhibitors at low doses could be of benefit for myeloma cells beyond the single selective inhibition of BCL2 or MCL1.

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Apoptosis is a highly conserved mechanism enabling the removal of unwanted cells. Mitochondrial apoptosis is governed by the B-cell lymphoma (BCL-2) family, including anti-apoptotic and pro-apoptotic proteins. Apoptosis evasion by dysregulation of anti-apoptotic BCL-2 members (BCL-2, MCL-1, BCL-X) is a common hallmark in cancers.

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Multiple myeloma (MM) arises from malignant immunoglobulin (Ig)-secreting plasma cells and remains an incurable, often lethal disease despite therapeutic advances. The unfolded-protein response sensor IRE1α supports protein secretion by deploying a kinase-endoribonuclease module to activate the transcription factor XBP1s. MM cells may co-opt the IRE1α-XBP1s pathway; however, the validity of IRE1α as a potential MM therapeutic target is controversial.

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BCL2-family proteins have a central role in the mitochondrial apoptosis machinery and their expression is known to be deregulated in many cancer types. Effort in the development of small molecules that selectively target anti-apoptotic members of this family i.e.

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Background: Human myeloma cell lines (HMCLs) are widely used for their representation of primary myeloma cells because they cover patient diversity, although not fully. Their genetic background is mostly undiscovered, and no comprehensive study has ever been conducted in order to reveal those details.

Methods: We performed whole-exon sequencing of 33 HMCLs, which were established over the last 50 years in 12 laboratories.

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BH3 mimetics are promising drugs for hematologic malignancies that trigger cell death by promoting the release of proapoptotic BCL2 family members from antiapoptotic proteins. Multiple myeloma is considered to be a disease dependent mainly on MCL1 for survival, based mostly on studies using cell lines. We used a BH3-mimetic toolkit to study the dependency on BCL2, BCLXL, or MCL1 in malignant plasma cells from 60 patients.

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As myeloma cells actively produce and secrete immunoglobulins, they are prone to ER stress, which if unresolved leads to apoptosis. We found that myeloma cell death induced by the ER stressor Thapsigargin was highly variable, ranging from 2 to 89%. Induction of ATF4 and CHOP was observed in myeloma cells under Thapsigargin independently of cell death.

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Multiple myeloma (MM) evolves from a premalignant condition known as monoclonal gammopathy of undetermined significance (MGUS). However, the factors underlying the malignant transformation of plasmocytes in MM are not fully characterized. We report here that Eµ-directed expression of the antiapoptotic Bcl-B protein in mice drives an MM phenotype that reproduces accurately the human disease.

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Due to its cytotoxic effect in lymphoid cells, dexamethasone is widely used in the treatment of multiple myeloma (MM). However, only a subset of myeloma patients responds to high-dose dexamethasone. Despite the undeniable anti-myeloma benefits of dexamethasone, significant adverse effects have been reported.

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Multiple myeloma (MM), a plasma cell malignancy, remains incurable despite the development of new therapies. Curcumin anti-tumor effects were previously characterized in multiple myeloma, however only few MM cell lines were included in these studies. Since myeloma is a heterogeneous disease it is important to address the impact of myeloma molecular heterogeneity in curcumin cell death induction.

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Background: The aim of this study was to evaluate the efficacy of the p53-reactivating drugs RITA and nutlin3a in killing myeloma cells.

Methods: A large cohort of myeloma cell lines (n = 32) and primary cells (n = 21) was used for this study. This cohort contained cell lines with various TP53 statuses and primary cells with various incidences of deletion of chromosome 17.

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Multiple myeloma (MM) is a plasma-cell (PC) malignancy that is heterogeneous in its clinical presentation and prognosis. Monoclonal gammopathy of undetermined significance (MGUS) consistently preceded development of MM. The presence of primary IgH translocations and the universal overexpression of cyclin D genes led to a molecular classification of MM patients into different disease subtypes.

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Myeloma cells are sensitive to TRAIL through the two death receptors DR4 and DR5. Because p53 directly modulates expression of death receptors, we investigated here whether p53 can modulate myeloma sensitivity to TRAIL. We found that p53 affects the sensitivity of myeloma cells to the DR5 agonistic human antibody lexatumumab but not the DR4 antibody mapatumumab.

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The level of the Mcl-1 pro-survival protein is highly regulated, and the down-regulation of Mcl-1 expression favors the apoptotic process. Mcl-1 physically interacts with different BH3-only proteins; particularly, Noxa is involved in the modulation of Mcl-1 expression. In this study, we demonstrated that Noxa triggers the degradation of Mcl-1 at the mitochondria according to the exclusive location of Noxa at this compartment.

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Multiple myeloma is a plasma cell malignancy that is heterogeneous with respect to its causative molecular abnormalities and the treatment response of patients. The Bcl-2 protein family is critical for myeloma cell survival. ABT-737 is a cell-permeant compound that binds to Bcl-2 and Bcl-x(L) but not to Mcl-1.

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Purpose: Mantle cell lymphoma (MCL) is considered to be incurable. ABT-737 is a BH3 mimetic that targets Bcl-2, which is overexpressed in MCL and implicated in drug resistance. The present work investigated the antitumor effect of ABT-737.

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Mcl-1 full-length (Mcl-1(1-350)), a tightly regulated protein, plays an important role in protecting cells against apoptosis. Cleavage of Mcl-1 at Asp127 by caspase (Mcl-1(C1)) contributes to the regulation of Mcl-1 expression, but its pro-apoptotic function remains controversial. Here, we reported that Mcl-1(128-350) expression induced caspase-dependent apoptosis.

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Survival of multiple myeloma cells is essentially dependent on Mcl-1 protein that neutralizes the pro-apoptotic function of Bim and prevents activation of death effectors. To clarify the relationship between Mcl-1 and Bim, we generated cell lines silenced for Mcl-1 (shMcl-1) or Bim (shBim). We demonstrate that Mcl-1 and Bim proteins are concomitantly down-regulated in either shBim or shMcl-1 cells.

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