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2.
Blood ; 141(11): 1308-1315, 2023 03 16.
Article de Anglais | MEDLINE | ID: mdl-36375118

RÉSUMÉ

Cytogenetic abnormalities (CAs) are known to be the preponderant prognostic factor in multiple myeloma. Our team has recently developed a prognostic score based on 6 CAs, with which del(1p32) appears to be the second worst abnormality after del(17p). This study aimed to confirm the adverse effect of 1p32 deletion in patients with newly diagnosed multiple myeloma (NDMM). Among 2551 patients with newly diagnosed multiple myeloma, 11% were harboring del(1p32). Their overall survival (OS) was significantly inferior compared with patients without del(1p32) (median OS: 49 months vs 124 months). Likewise, progression-free survival was significantly shorter. More importantly, biallelic del(1p32) conferred a dramatically poorer prognosis than a monoallelic del(1p32) (median OS: 25 months vs 60 months). As expected, the OS of patients with del(1p32) significantly decreased when this abnormality was associated with other high-risk CAs [del(17p), t(4;14), or gain(1q)]. In the multivariate analysis, del(1p32) appeared as a negative prognostic factor; after adjustment for age and treatment, the risk of progression was 1.3 times higher among patients harboring del(1p32), and the risk of death was 1.9 times higher. At the dawn of risk-adapted treatment strategies, we have confirmed the adverse effect of del(1p32) in multiple myeloma and the relevance of its assessment at diagnosis.


Sujet(s)
Myélome multiple , Humains , Myélome multiple/diagnostic , Myélome multiple/génétique , Pronostic , Aberrations des chromosomes , Hybridation fluorescente in situ , Survie sans progression
3.
Blood ; 139(17): 2666-2672, 2022 04 28.
Article de Anglais | MEDLINE | ID: mdl-35171994

RÉSUMÉ

Primary plasma cell leukemia (pPCL) is an aggressive form of multiple myeloma (MM) that has not benefited from recent therapeutic advances in the field. Because it is very rare and heterogeneous, it remains poorly understood at the molecular level. To address this issue, we performed DNA and RNA sequencing of sorted plasma cells from a large cohort of 90 newly diagnosed pPCL and compared with MM. We observed that pPCL presents a specific genomic landscape with a high prevalence of t(11;14) (about half) and high-risk genomic features such as del(17p), gain 1q, and del(1p32). In addition, pPCL displays a specific transcriptome when compared with MM. We then wanted to characterize specifically pPCL with t(11;14). We observed that this subentity displayed significantly fewer adverse cytogenetic abnormalities. This translated into better overall survival when compared with pPCL without t(11;14) (39.2 months vs 17.9 months, P = .002). Finally, pPCL with t(11;14) displayed a specific transcriptome, including differential expression of BCL2 family members. This study is the largest series of patients with pPCL reported so far.


Sujet(s)
Leucémie à plasmocytes , Myélome multiple , Aberrations des chromosomes , Génomique , Humains , Leucémie à plasmocytes/diagnostic , Myélome multiple/génétique , Pronostic , Transcriptome
4.
Blood ; 137(9): 1192-1195, 2021 03 04.
Article de Anglais | MEDLINE | ID: mdl-33080624

RÉSUMÉ

Despite tremendous improvements in the outcome of patients with multiple myeloma in the past decade, high-risk patients have not benefited from the approval of novel drugs. The most important prognostic factor is the loss of parts of the short arm of chromosome 17, known as deletion 17p (del(17p)). A recent publication (on a small number of patients) suggested that these patients are at very high-risk only if del(17p) is associated with TP53 mutations, the so-called "double-hit" population. To validate this finding, we designed a much larger study on 121 patients presenting del(17p) in > 55% of their plasma cells, and homogeneously treated by an intensive approach. For these 121 patients, we performed deep next generation sequencing targeted on TP53. The outcome was then compared with a large control population (2505 patients lacking del(17p)). Our results confirmed that the "double hit" situation is the worst (median survival = 36 months), but that del(17p) alone also confers a poor outcome compared with the control cohort (median survival = 52.8 months vs 152.2 months, respectively). In conclusion, our study clearly confirms the extremely poor outcome of patients displaying "double hit," but also that del(17p) alone is still a very high-risk feature, confirming its value as a prognostic indicator for poor outcome.


Sujet(s)
Délétion de segment de chromosome , Chromosomes humains de la paire 17/génétique , Myélome multiple/génétique , Protéine p53 suppresseur de tumeur/génétique , Adulte , Sujet âgé , Femelle , Humains , Mâle , Adulte d'âge moyen , Myélome multiple/diagnostic , Mutation , Pronostic , Jeune adulte
5.
Immunity ; 53(4): 824-839.e10, 2020 10 13.
Article de Anglais | MEDLINE | ID: mdl-33053331

RÉSUMÉ

CD8+ T cells within the tumor microenvironment (TME) are exposed to various signals that ultimately determine functional outcomes. Here, we examined the role of the co-activating receptor CD226 (DNAM-1) in CD8+ T cell function. The absence of CD226 expression identified a subset of dysfunctional CD8+ T cells present in peripheral blood of healthy individuals. These cells exhibited reduced LFA-1 activation, altered TCR signaling, and a distinct transcriptomic program upon stimulation. CD226neg CD8+ T cells accumulated in human and mouse tumors of diverse origin through an antigen-specific mechanism involving the transcriptional regulator Eomesodermin (Eomes). Despite similar expression of co-inhibitory receptors, CD8+ tumor-infiltrating lymphocyte failed to respond to anti-PD-1 in the absence of CD226. Immune checkpoint blockade efficacy was hampered in Cd226-/- mice. Anti-CD137 (4-1BB) agonists also stimulated Eomes-dependent CD226 loss that limited the anti-tumor efficacy of this treatment. Thus, CD226 loss restrains CD8+ T cell function and limits the efficacy of cancer immunotherapy.


Sujet(s)
Antigènes de différenciation des lymphocytes T/immunologie , Lymphocytes T CD8+/immunologie , Tumeurs/immunologie , Protéines à domaine boîte-T/immunologie , Animaux , Humains , Inhibiteurs de points de contrôle immunitaires/immunologie , Immunothérapie/méthodes , Souris , Souris de lignée C57BL , Tumeurs/thérapie , Récepteur-1 de mort cellulaire programmée/immunologie , Récepteurs aux antigènes des cellules T/immunologie , Transduction du signal/immunologie , Transcriptome/immunologie , Microenvironnement tumoral/immunologie , Antigènes CD137/immunologie
8.
Leukemia ; 32(12): 2636-2647, 2018 12.
Article de Anglais | MEDLINE | ID: mdl-29895955

RÉSUMÉ

Clonal evolution drives tumor progression, chemoresistance and relapse in cancer. Little is known about clonal selection induced by therapeutic pressure in multiple myeloma. To address this issue, we performed large targeted sequencing of bone marrow plasma cells in 43 multiple myeloma patients at diagnosis and at relapse from exactly the same intensive treatment. The most frequently mutated genes at diagnosis were KRAS (35%), NRAS (28%), DIS3 (16%), BRAF, and LRP1B (12% each). At relapse, the mutational burden was unchanged. Many of the mutations were present at the subclonal level at both time points, including driver ones. According to patients and mutations, we observed different scenarios: selection of a very rare subclone present at diagnosis, appearance, or disappearance of mutations, but also stability. Our data highlight that chemoresistance and relapse could be induced by newly acquired mutations in myeloma drivers but also by (sub)clonal mutations preexisting to the treatment. Importantly, no specific mutation or rearrangement was observed at relapse, demonstrating that intensive treatment has a nonspecific effect on clonal selection in multiple myeloma. Finally, we identified 22 cases of biallelic event, including a double event deletion 17p/TP53mut.


Sujet(s)
Évolution clonale/génétique , Myélome multiple/génétique , Myélome multiple/anatomopathologie , Sujet âgé , Moelle osseuse/anatomopathologie , Résistance aux médicaments antinéoplasiques/génétique , Femelle , Humains , Mâle , Adulte d'âge moyen , Mutation/génétique , Récidive tumorale locale/génétique , Récidive tumorale locale/anatomopathologie
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