RESUMO
NOTCH1 PEST domain mutations are often seen in hematopoietic malignancies, including T-cell acute lymphoblastic leukemia (T-ALL), chronic lymphocytic leukemia (CLL), splenic marginal zone lymphoma (SMZL), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL). These mutations play a key role in the development and progression of lymphoproliferative tumors by increasing the Notch signaling and, consequently, promoting cell proliferation, survival, migration, and suppressing apoptosis. There is currently no specific treatment available for cancers caused by NOTCH1 PEST domain mutations. However, several NOTCH1 inhibitors are in development. Among these, inhibition of the Sarco-endoplasmic Ca2+-ATPase (SERCA) showed a greater effect in NOTCH1-mutated tumors compared to the wild-type ones. One example is CAD204520, a benzimidazole derivative active in T-ALL cells harboring NOTCH1 mutations. In this study, we preclinically assessed the effect of CAD204520 in CLL and MCL models and showed that NOTCH1 PEST domain mutations sensitize cells to the anti-leukemic activity mediated by CAD204520. Additionally, we tested the potential of CAD204520 in combination with the current first-line treatment of CLL, venetoclax, and ibrutinib. CAD204520 enhanced the synergistic effect of this treatment regimen only in samples harboring the NOTCH1 PEST domain mutations, thus supporting a role for Notch inhibition in these tumors. In summary, our work provides strong support for the development of CAD204520 as a novel therapeutic approach also in chronic lymphoproliferative disorders carrying NOTCH1 PEST domain mutations, emerging as a promising molecule for combination treatment in this aggressive subset of patients.
Assuntos
Neoplasias Hematológicas , Leucemia Linfocítica Crônica de Células B , Transtornos Linfoproliferativos , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/genética , Transtornos Linfoproliferativos/tratamento farmacológico , Transtornos Linfoproliferativos/genética , Mutação , Receptor Notch1/genéticaRESUMO
The overexpression of the ecotropic viral integration site-1 gene (EVI1/MECOM) marks the most lethal acute myeloid leukemia (AML) subgroup carrying chromosome 3q26 abnormalities. By taking advantage of the intersectionality of high-throughput cell-based and gene expression screens selective and pan-histone deacetylase inhibitors (HDACis) emerge as potent repressors of EVI1. To understand the mechanism driving on-target anti-leukemia activity of this compound class, here we dissect the expression dynamics of the bone marrow leukemia cells of patients treated with HDACi and reconstitute the EVI1 chromatin-associated co-transcriptional complex merging on the role of proliferation-associated 2G4 (PA2G4) protein. PA2G4 overexpression rescues AML cells from the inhibitory effects of HDACis, while genetic and small molecule inhibition of PA2G4 abrogates EVI1 in 3q26 AML cells, including in patient-derived leukemia xenografts. This study positions PA2G4 at the crosstalk of the EVI1 leukemogenic signal for developing new therapeutics and urges the use of HDACis-based combination therapies in patients with 3q26 AML.
Assuntos
Cromossomos Humanos Par 3 , Inibidores de Histona Desacetilases , Leucemia Mieloide Aguda , Proteína do Locus do Complexo MDS1 e EVI1 , Proteogenômica , Animais , Feminino , Humanos , Camundongos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Cromossomos Humanos Par 3/genética , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Proteína do Locus do Complexo MDS1 e EVI1/metabolismo , Proteína do Locus do Complexo MDS1 e EVI1/genética , Proteogenômica/métodos , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Ensaios Antitumorais Modelo de XenoenxertoAssuntos
Púrpura Trombocitopênica Idiopática/terapia , Terapia de Salvação/métodos , Sirolimo/uso terapêutico , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Masculino , Ácido Micofenólico/farmacologia , Ácido Micofenólico/uso terapêutico , Estudos Retrospectivos , Serina-Treonina Quinases TOR/antagonistas & inibidores , Resultado do Tratamento , Adulto JovemRESUMO
Anti-CD19 chimeric antigen receptor (CAR) T cells represent the first approved third-line therapy associated with long-term remissions in patients with refractory/relapsed (R/R) diffuse large B-cell lymphoma (DLBCL). Eligibility criteria to identify patients who can successfully receive CAR-T are still debated. For this reason, the aim of this study was to identify factors influencing eligibility and define a realistic patient estimate. Of 1100 DLBCL patients, 137 were included. Based on the Juliet trial inclusion criteria, only 64 patients (46.7%) would be eligible. Median overall survival (OS) was 8.04 months in eligible vs 3.23 in non-eligible patients (p < 0.001). Multivariate analysis identified stage III-IV (p = 0.017) and ECOG ≥2 (p < 0.001) as significant independent prognostic factors for OS. Moreover, only 64/1100 (5.8%) DLBCL patients would be truly eligible for CAR-T. Our real-life data confirm that with a longer waiting time patients with advanced stage and poor ECOG are less likely to be eligible for CAR-T cell infusion.