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1.
Am J Hematol ; 98(1): 56-65, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36216791

RESUMO

Chronic lymphocytic leukemia (CLL) transformation to aggressive lymphoma, known as Richter's Transformation (RT), has a dismal prognosis. There are limited data evaluating risk of RT in patients treated with ibrutinib. We performed a retrospective analysis to determine prognostic variables associated with development of RT and overall survival (OS) at progression after treatment with ibrutinib. We identified 559 patients with CLL treated with ibrutinib from 2010-2019. After a median follow-up of 44.5 months from ibrutinib start, 179 patients progressed and were included in our analysis. After a median follow-up of 20.8 months from progression, 54 out of 179 patients developed RT. Progression on treatment (hazard ratio [HR] 4.01 [1.60-10.00], p = .003), higher LDH (HR 1.80 for 2-fold increase [1.33-2.43], p = .0001), and lymphadenopathy without lymphocytosis (HR 2.88 [1.15-7.20], p = .02) were independent prognostic variables for the development of RT at progression. Progression with lymphadenopathy without lymphocytosis continued to be an independent prognostic variable of worse OS post-progression. In a subset analysis of 50 patients who obtained a PET-CT at progression, the median SUVmax for patients who would develop RT was 15.2 (n = 30, range: 4.0-46.3) versus those patients who did not develop RT with a SUVmax of 7.7 (n = 20, range: 2.3-27.2) (p = .0030). Median OS from date of RT was 4.0 months, suggesting that prognosis for RT remains poor. A lymph node biopsy to rule out RT should be considered in patients who received ibrutinib who progress on treatment, have an elevated LDH, or progress with lymphadenopathy without lymphocytosis.


Assuntos
Leucemia Linfocítica Crônica de Células B , Linfadenopatia , Linfocitose , Linfoma Difuso de Grandes Células B , Humanos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Estudos Retrospectivos
2.
Blood ; 131(7): 771-781, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29180399

RESUMO

MicroRNA (miRNA) dysregulation is a hallmark of cutaneous T-cell lymphoma (CTCL), an often-fatal malignancy of skin-homing CD4+ T cells for which there are few effective therapies. The role of microRNAs (miRs) in controlling epigenetic modifier-dependent transcriptional regulation in CTCL is unknown. In this study, we characterize a novel miR dysregulation that contributes to overexpression of the epigenetic reader bromodomain-containing protein 4 (BRD4). We used patient CD4+ T cells to show diminished levels of miR-29b compared with healthy donor cells. Patient cells and miR-29b-/- mouse cells revealed an inverse relationship between miR-29b and BRD4, the latter of which is overexpressed in these cells. Chromatin immunoprecipitation and sequencing analysis revealed increased genome-wide BRD4 occupancy at promoter and enhancer regions in CD4+ T cells from CTCL patients. The cumulative result of BRD4 binding was increased expression of tumor-associated genes such as NOTCH1 and RBPJ, as well as the interleukin-15 (IL-15) receptor complex, the latter enhancing IL-15 autocrine signaling. Furthermore, we confirm the in vivo relevance of this pathway in our IL-15 transgenic mouse model of CTCL by showing that interference with BRD4-mediated pathogenesis, either by restoring miR-29b levels via bortezomib treatment or by directly inhibiting BRD4 binding via JQ1 treatment, prevents progression of CTCL. We describe a novel oncogenic pathway featuring IL-15, miR-29b, and BRD4 in CTCL and suggest targeting of these components as a potentially effective therapy for CTCL patients.


Assuntos
Linfoma Cutâneo de Células T/genética , MicroRNAs/genética , Proteínas Nucleares/fisiologia , Oncogenes/genética , Neoplasias Cutâneas/genética , Fatores de Transcrição/fisiologia , Animais , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Proteínas de Ciclo Celular , Células Cultivadas , Regulação para Baixo/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Linfoma Cutâneo de Células T/imunologia , Linfoma Cutâneo de Células T/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Ativação Transcricional
3.
Cancers (Basel) ; 14(23)2022 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-36497266

RESUMO

Immunotherapy approaches have advanced rapidly in recent years. While the greatest therapeutic advances so far have been achieved with T cell therapies such as immune checkpoint blockade and CAR-T, recent advances in NK cell therapy have highlighted the therapeutic potential of these cells. Chronic lymphocytic leukemia (CLL), the most prevalent form of leukemia in Western countries, is a very immunosuppressive disease but still shows significant potential as a target of immunotherapy, including NK-based therapies. In addition to their antileukemia potential, NK cells are important immune effectors in the response to infections, which represent a major clinical concern for CLL patients. Here, we review the interactions between NK cells and CLL, describing functional changes and mechanisms of CLL-induced NK suppression, interactions with current therapeutic options, and the potential for therapeutic benefit using NK cell therapies.

4.
Blood Adv ; 6(18): 5440-5448, 2022 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-35759759

RESUMO

Cytotoxic T lymphocyte antigen 4 (CTLA4) is a major immune checkpoint and target for cancer immunotherapy. Although originally discovered and primarily studied on T cells, its role on other cell types has also been recognized in recent years. Here we describe an unexpected interaction between ibrutinib (a targeted inhibitor of Bruton tyrosine kinase [BTK]) and CTLA4 expression on malignant chronic lymphocytic leukemia (CLL) cells. Although BTK itself does play a role in CTLA4 expression in CLL, we demonstrate that ibrutinib's main suppressive effect on CTLA4 protein expression and trafficking occurs through non-BTK targets influenced by this drug. This suppression is not seen in T cells, indicating a different mechanism of CTLA4 regulation in CLL vs T cells. Appreciating this distinct mechanism and the beneficial non-BTK effects of ibrutinib may contribute to understanding the immune benefits of ibrutinib treatment and lead to therapeutic approaches to improve immune function in patients with CLL by suppressing CTLA4 expression.


Assuntos
Leucemia Linfocítica Crônica de Células B , Tirosina Quinase da Agamaglobulinemia , Antígeno CTLA-4/genética , Antígeno CTLA-4/uso terapêutico , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/metabolismo , Proteínas Tirosina Quinases , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico
5.
Blood Adv ; 6(20): 5641-5654, 2022 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-35486482

RESUMO

Successes with anti-CD20 antibodies in chronic lymphocytic leukemia (CLL) and enhanced activity of Fc-engineered vs unmodified antibody therapy suggest a potentially impactful role for natural killer (NK) cells and other innate immune cells in controlling this disease. Stimulated NK cells have shown promise as a cellular therapy, but their application has been constrained by limited expansion capacity and low cytotoxic activity against CLL cells. Here, we demonstrate that both healthy donor-derived and CLL patient-derived NK cells expand rapidly when stimulated with feeder cells expressing membrane-bound interleukin-21 (mbIL-21) and have potent cytotoxic activity against allogeneic or autologous CLL cells. Combination with anti-CD20 antibodies significantly enhances NK recognition and killing of CLL targets. As any CLL immune therapy would likely be given in combination, we assess commonly used treatments and demonstrate that ibrutinib has mixed suppressive and protective effects on expanded NK cells, whereas expanded NKs are highly resistant to venetoclax. We demonstrate efficacy in vivo in 2 xenograft mouse models of human CLL that support building upon a regimen of venetoclax and obinutuzumab with mbIL-21-expanded NK cells. Collectively, these data support development of mbIL-21-expanded NKs combined with the CD20 antibody obinutuzumab and venetoclax in the treatment of CLL.


Assuntos
Antineoplásicos , Transplante de Células-Tronco Hematopoéticas , Leucemia Linfocítica Crônica de Células B , Animais , Humanos , Camundongos , Antineoplásicos/uso terapêutico , Células Matadoras Naturais , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico
6.
Nat Commun ; 12(1): 6338, 2021 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-34732719

RESUMO

Rare, recurrent balanced translocations occur in a variety of cancers but are often not functionally interrogated. Balanced translocations with the immunoglobulin heavy chain locus (IGH; 14q32) in chronic lymphocytic leukemia (CLL) are infrequent but have led to the discovery of pathogenic genes including CCND1, BCL2, and BCL3. Following identification of a t(X;14)(q28;q32) translocation that placed the mature T cell proliferation 1 gene (MTCP1) adjacent to the immunoglobulin locus in a CLL patient, we hypothesized that this gene may have previously unrecognized importance. Indeed, here we report overexpression of human MTCP1 restricted to the B cell compartment in mice produces a clonal CD5+/CD19+ leukemia recapitulating the major characteristics of human CLL and demonstrates favorable response to therapeutic intervention with ibrutinib. We reinforce the importance of genetic interrogation of rare, recurrent balanced translocations to identify cancer driving genes via the story of MTCP1 as a contributor to CLL pathogenesis.


Assuntos
Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Translocação Genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Proteína 3 do Linfoma de Células B , Ciclina D1 , Feminino , Regulação da Expressão Gênica , Genes de Cadeia Pesada de Imunoglobulina , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Oncogenes/genética , Proteínas Proto-Oncogênicas c-bcl-2
7.
Blood Adv ; 3(8): 1255-1266, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-30987970

RESUMO

Prostate apoptosis response 4 (Par-4) is a tumor suppressor that prevents proliferation and induces cell death in several solid tumors. However, its role in B-cell malignancies has not been elucidated. To describe the role of Par-4 in chronic lymphocytic leukemia (CLL) pathogenesis, we developed a B-cell-specific human Par-4-overexpressing mouse model of CLL using the TCL1 leukemia model. While Par-4 transgenic mice did not display any obvious defects in B-cell development or function, disease burden as evidenced by abundance of CD19+CD5+ B cells in the peripheral blood was significantly reduced in Par-4 × TCL1 mice compared with TCL1 littermates. This conferred a survival advantage on the Par-4-overexpressing mice. In addition, a B-cell-specific knockout model displayed the opposite effect, where lack of Par-4 expression resulted in accelerated disease progression and abbreviated survival in the TCL1 model. Histological and flow cytometry-based analysis of spleen and bone marrow upon euthanasia revealed comparable levels of malignant B-cell infiltration in Par-4 × TCL1 and TCL1 individuals, indicating delayed but pathologically normal disease progression in Par-4 × TCL1 mice. In vivo analysis of splenic B-cell proliferation by 5-ethynyl-2-deoxyuridine incorporation indicated >50% decreased expansion of CD19+CD5+ cells in Par-4 × TCL1 mice compared with TCL1 littermates. Moreover, reduced nuclear p65 levels were observed in Par-4 × TCL1 splenic B cells compared with TCL1, suggesting suppressed NF-κB signaling. These findings have identified an in vivo antileukemic role for Par-4 through an NF-κB-dependent mechanism in TCL1-mediated CLL-like disease progression.


Assuntos
Proteínas Reguladoras de Apoptose/biossíntese , Carcinogênese/metabolismo , Leucemia Linfocítica Crônica de Células B/metabolismo , Neoplasias Experimentais/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais , Proteínas Supressoras de Tumor/metabolismo , Animais , Carcinogênese/genética , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Camundongos , Camundongos Transgênicos , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Proteínas Proto-Oncogênicas/genética , Proteínas Supressoras de Tumor/genética
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