RESUMO
Somatic mosaic states in telomere biology disorders are characterized by somatic variants in the spliceosome and DNA damage response and repair pathways. A likely maladaptive response to short telomeres that may lead to increased hematological cancer.
Assuntos
Telomerase , Telômero , Humanos , Fator de Processamento U2AF/genética , Telômero/genética , Telômero/metabolismo , Biologia , Telomerase/genética , Telomerase/metabolismoRESUMO
PURPOSE: Preclinical studies in myeloid neoplasms have demonstrated efficacy of bromodomain and extra-terminal protein inhibitors (BETi). However, BETi demonstrates poor single-agent activity in clinical trials. Several studies suggest that combination with other anticancer inhibitors may enhance the efficacy of BETi. EXPERIMENTAL DESIGN: To nominate BETi combination therapies for myeloid neoplasms, we used a chemical screen with therapies currently in clinical cancer development and validated this screen using a panel of myeloid cell line, heterotopic cell line models, and patient-derived xenograft models of disease. We used standard protein and RNA assays to determine the mechanism responsible for synergy in our disease models. RESULTS: We identified PIM inhibitors (PIMi) as therapeutically synergistic with BETi in myeloid leukemia models. Mechanistically, we show that PIM kinase is increased after BETi treatment, and that PIM kinase upregulation is sufficient to induce persistence to BETi and sensitize cells to PIMi. Furthermore, we demonstrate that miR-33a downregulation is the underlying mechanism driving PIM1 upregulation. We also show that GM-CSF hypersensitivity, a hallmark of chronic myelomonocytic leukemia (CMML), represents a molecular signature for sensitivity to combination therapy. CONCLUSIONS: Inhibition of PIM kinases is a potential novel strategy for overcoming BETi persistence in myeloid neoplasms. Our data support further clinical investigation of this combination.
Assuntos
Leucemia Mielomonocítica Crônica , MicroRNAs , Humanos , Linhagem Celular Tumoral , Proteínas , MicroRNAs/genética , MicroRNAs/metabolismoRESUMO
Myeloid neoplasms are clonal hematopoietic stem cell disorders driven by the sequential acquisition of recurrent genetic lesions. Truncating mutations in the chromatin remodeler ASXL1 (ASXL1MT) are associated with a high-risk disease phenotype with increased proliferation, epigenetic therapeutic resistance, and poor survival outcomes. We performed a multi-omics interrogation to define gene expression and chromatin remodeling associated with ASXL1MT in chronic myelomonocytic leukemia (CMML). ASXL1MT are associated with a loss of repressive histone methylation and increase in permissive histone methylation and acetylation in promoter regions. ASXL1MT are further associated with de novo accessibility of distal enhancers binding ETS transcription factors, targeting important leukemogenic driver genes. Chromatin remodeling of promoters and enhancers is strongly associated with gene expression and heterogenous among overexpressed genes. These results provide a comprehensive map of the transcriptome and chromatin landscape of ASXL1MT CMML, forming an important framework for the development of novel therapeutic strategies targeting oncogenic cis interactions.
Assuntos
Leucemia Mielomonocítica Crônica , Epigênese Genética , Expressão Gênica , Humanos , Leucemia Mielomonocítica Crônica/genética , Leucemia Mielomonocítica Crônica/patologia , Mutação , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoAssuntos
Trombocitemia Essencial/genética , Trombose/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Calreticulina/genética , Feminino , Humanos , Janus Quinase 2/genética , Masculino , Pessoa de Meia-Idade , Mutação , Receptores de Trombopoetina/genética , Trombocitemia Essencial/complicações , Trombose/etiologia , Adulto JovemAssuntos
Leucemia Mielomonocítica Crônica/genética , Receptores de Fator Estimulador de Colônias/genética , Proteínas Repressoras/genética , Adulto , Idoso , Proliferação de Células , Feminino , Humanos , Leucemia Mielomonocítica Crônica/diagnóstico , Masculino , Pessoa de Meia-Idade , Mutação , PrognósticoAssuntos
Mutação , Síndromes Mielodisplásicas/genética , Transtornos Mieloproliferativos/genética , Proteínas ras/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Criança , Pré-Escolar , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/patologia , Transtornos Mieloproliferativos/patologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Adulto JovemAssuntos
Códon sem Sentido , Proteínas de Ligação a DNA/genética , Mutação da Fase de Leitura , Estudos de Associação Genética , Síndromes Mielodisplásicas/genética , Transtornos Mieloproliferativos/genética , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogênicas/genética , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Dioxigenases , Progressão da Doença , Seguimentos , Humanos , Lactente , Leucemia Mielogênica Crônica BCR-ABL Positiva/epidemiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/mortalidade , Transtornos Mieloproliferativos/sangue , Transtornos Mieloproliferativos/mortalidade , Prognóstico , Análise de Sobrevida , Resultado do TratamentoRESUMO
Survival prediction in essential thrombocythaemia (ET) and polycythaemia vera (PV) is currently based on clinically-derived variables; we examined the possibility of integrating genetic information for predicting survival. To this end, 906 molecularly-annotated patients (416 Mayo Clinic; 490 University of Florence, Italy), including 502 ET and 404 PV, were recruited. Multivariable analysis identified spliceosome mutations to adversely affect overall (SF3B1, SRSF2 in ET and SRSF2 in PV) and myelofibrosis-free (U2AF1, SF3B1 in ET) survival; TP53 mutations predicted leukaemic transformation in ET; "adverse" mutations occurred in 51 (10%) ET and 8 (2%) PV patients. We confirmed the independent survival effect of adverse mutations [hazard ratio (HR) 2·4, 95% CI 1·6-3·5], age >60 years (6·6, 4·6-9·7), male sex (1·8, 1·3-2·4) and leukocytosis ≥11 × 109 /l (1·6, 1·1-2·2), in ET, and adverse mutations (7·8, 3·1-17·0), age >67 years (5·4, 3·6-8·1), leukocytosis ≥15 × 109 /l (2·8, 1·8-4·2) and thrombosis history (2·0, 1·4-2·9), in PV. HR-based risk point allocation allowed development of three-tiered mutation-enhanced international prognostic systems (MIPSS) which were validated in both cohorts and performance was shown to be superior to conventional scoring systems. Spliceosome mutations enhance survival prediction in ET and PV and identify patients at risk for fibrotic progression. TP53 mutations predict leukaemic transformation in ET.
Assuntos
Policitemia Vera/genética , Trombocitemia Essencial/genética , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , PrognósticoRESUMO
Loss-of-function TET2 mutations (TET2MT) are frequent early clonal events in myeloid neoplasms and are thought to confer a fitness advantage to hematopoietic precursors. This large, multi-institutional study (n = 1084), investigated the TET2 mutational landscape and prognostic implications of the number, type, and location of TET2MT and the epistatic relationship with other somatic events in chronic myelomonocytic leukemia (CMML). Nine hundred and forty-two TET2MT were identified in 604 (56%) patients, of which 710 (75%) were predicted to be truncating (involving the catalytic domain). Three hundred and sixteen (29%) patients had ≥1 TET2MT, with 28%, 1%, and 0.2% harboring 2, 3, and 5 mutations, respectively. In comparison to TET2WT, TET2MT patients were older in age, more likely to have dysplastic CMML, a higher number of co-occurring mutations, and lower-risk stratification. Importantly, TET2MT were associated with a survival advantage (49 vs. 30 months, p < 0.0001), especially in the context of multiple TET2MT (≥2; 57 months, p < 0.001), and truncating TET2MT (51 months, p < 0.001). In addition, the adverse prognostic impact of ASXL1MT was partially mitigated by concurrent TET2MT, with the ASXL1WT/TET2MT genotype having better outcomes and resulting in further risk stratification of ASXL1 inclusive CMML prognostic models, in comparison to ASXL1MT alone.
Assuntos
Biomarcadores Tumorais/genética , Proteínas de Ligação a DNA/genética , Regulação Leucêmica da Expressão Gênica , Leucemia Mielomonocítica Crônica/patologia , Mutação , Proteínas Proto-Oncogênicas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Dioxigenases , Feminino , Seguimentos , Humanos , Leucemia Mielomonocítica Crônica/genética , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Adulto JovemAssuntos
Neoplasias da Medula Óssea/genética , Isocitrato Desidrogenase/genética , Mutação , Síndromes Mielodisplásicas/genética , Transtornos Mieloproliferativos/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Medula Óssea/epidemiologia , Estudos de Casos e Controles , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/fisiologia , Síndromes Mielodisplásicas/epidemiologia , Transtornos Mieloproliferativos/epidemiologia , Análise de SobrevidaAssuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Mutação em Linhagem Germinativa , Neoplasias Hematológicas/genética , Doenças Mieloproliferativas-Mielodisplásicas/genética , Proteínas de Neoplasias/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Mieloproliferativas-Mielodisplásicas/tratamento farmacológico , Doenças Mieloproliferativas-Mielodisplásicas/metabolismo , Doenças Mieloproliferativas-Mielodisplásicas/patologia , Proteínas de Neoplasias/metabolismoRESUMO
Hypomethylating agents (HMA) are currently the only FDA approved therapy for patients with chronic myelomonocytic leukemia (CMML). In the current retrospective study, we assessed response rates as adjudicated by the IWG (International Working Group) MDS (myelodysplastic syndrome) and MDS/MPN myeloproliferative neoplasm overlap syndrome response criteria, in 121 CMML patients treated with Azacitidine (AZA, n = 56) and Decitabine (DAC, n = 65). The overall response rates were 41% by the IWG MDS (AZA- 45%, DAC-39%), and 56% by the IWG MDS/MPN (AZA-56%, DAC-58%) response criteria, with CR (complete remission) rates of <20% for both agents, by both criteria. There were no significant differences in response rates between proliferative and dysplastic CMML. Moreover, 29% of CMML patients in a CR with HMA progressed to AML (blast transformation), underscoring the limited impact of these agents on disease biology. Progression after HMA response was associated with a median overall-survival (OS) of 8 months, while median OS in patients with primary HMA failure was 4 months. Lower serum LDH levels (<250 Units/L) were associated with HMA responses by both criteria; while ASXL1 and TET2 mutational status had no impact. HMA treated patients had a longer median OS (31 vs 18 months; P = .01), in comparison to those treated with conventional care regimens (excluding observation only patients), without any differences between AZA vs DAC (P = .37). In conclusion, this study highlights the inadequacies of HMA therapy in CMML, retrospectively validates the IWG MDS/MPN response criteria and underscores the need for newer, rationally derived therapies.
Assuntos
Azacitidina/administração & dosagem , Decitabina/administração & dosagem , Leucemia Mielogênica Crônica BCR-ABL Positiva , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Fatores de TempoAssuntos
Alelos , Substituição de Aminoácidos , Janus Quinase 2/genética , Leucemia Mielomonocítica Crônica/genética , Mutação , Biomarcadores , Biomarcadores Tumorais , Feminino , Testes Genéticos , Humanos , Leucemia Mielomonocítica Crônica/diagnóstico , Leucemia Mielomonocítica Crônica/mortalidade , Masculino , Estadiamento de Neoplasias , Prognóstico , Análise de SobrevidaRESUMO
Among 1306 patients with primary myelofibrosis (PMF), we sought to identify risk factors that predicted leukemic transformation (LT) in the first 5 years of disease and also over the course of the disease. 149 (11%) LT were documented; patients who subsequently developed LT (n = 149), compared to those who remained in chronic phase disease (n = 1,157), were more likely to be males (p = 0.02) and display higher circulating blasts (p = 0.03), ASXL1 (p = 0.01), SRSF2 (p = 0.001) and IDH1 (p = 0.02) mutations. Logistic regression analysis identified IDH1, ASXL1 and SRSF2 mutations, very high-risk karyotype, age > 70 years, male sex, circulating blasts ≥ 3%, presence of moderate or severe anemia and constitutional symptoms, as predictors of LT in the first 5 years of diagnosis. Time-to-event Cox analysis confirmed LT prediction for IDH1 mutation (HR 4.3), circulating blasts ≥ 3% (HR 3.3), SRSF2 mutation (HR 3.0), age > 70 years (HR 2.1), ASXL1 mutation (HR 2.0) and presence of moderate or severe anemia (HR 1.9). HR-based risk point allocation resulted in a three-tiered LT risk model: high-risk (LT incidence 57%; HR 39.3, 95% CI 10.8-114), intermediate-risk (LT incidence 17%; HR 4.1, 95% CI 2.4-7.3) and low-risk (LT incidence 8%). The current study provides a highly discriminating LT predictive model for PMF.
Assuntos
Transformação Celular Neoplásica , Leucemia/epidemiologia , Leucemia/etiologia , Mielofibrose Primária/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Progressão da Doença , Feminino , Humanos , Leucemia/mortalidade , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Mielofibrose Primária/patologia , Prognóstico , Medição de Risco , Fatores de Risco , Adulto JovemAssuntos
Antineoplásicos/uso terapêutico , Janus Quinase 2/antagonistas & inibidores , Transtornos Mieloproliferativos/sangue , Transtornos Mieloproliferativos/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Tiamina/sangue , Antineoplásicos/farmacologia , Humanos , Terapia de Alvo Molecular , Mutação , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/patologia , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/genética , Inibidores de Proteínas Quinases/farmacologia , Resultado do TratamentoRESUMO
JAK2 mutations in myeloproliferative neoplasms (MPNs) are associated with the germline GGCC (46/1) haplotype. In 2010, we reported an association between shortened survival in primary myelofibrosis (PMF) and nullizygosity for the JAK2 46/1 haplotype. In the current study, we have increased the number of informative cases from 130 to 414 (median age 63 years; 63% males), in order to revisit with the phenotypic and prognostic relevance of the JAK2 46/1 haplotype in PMF. JAK2 46/1 haplotype was documented in 69% of the study patients, including 25% in homozygous and 44% in heterozygous state. Driver mutation frequency in patients homozygous/heterozygous/nullizygous for the 46/1 haplotype was 78%/60%/56% JAK2, 10%/20%/18% type 1-like CALR, 3%/2%/5% type 2-like CALR, 4%/8%/7% MPL, and 6%/10%/14% triple-negative (P = .02). In univariate analysis, nullizygosity for the JAK2 46/1 haplotype was associated with inferior overall survival (HR 1.5, 95% CI 1.1-1.9), most pronounced in JAK2 (P <.001), as opposed to CALR/MPL mutated (P = .48) or triple-negative cases (P = .27). Multivariable analysis that included karyotype, driver mutational status and high-molecular risk mutations confirmed the independent prognostic contribution of nullizygosity for the 46/1 haplotype (P = .02; HR 1.4, 95% CI 1.1-1.8). Nullizygosity for 46/1 also remained significant in the context of the genetically-inspired GIPSS risk model (P = .04), but not in the context of the integrated genetics-clinical MIPSS70+ version 2.0 model (P = .4). Leukemia-free survival was not affected by the 46/1 haplotype (P = .6). The current study confirms the association of nullizygosity for the JAK2 GGCC (46/1) haplotype with inferior survival in JAK2-mutated PMF.
Assuntos
Calreticulina/genética , Mutação em Linhagem Germinativa , Janus Quinase 2/genética , Modelos Genéticos , Mielofibrose Primária/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Estudos de Coortes , Feminino , Expressão Gênica , Haplótipos , Heterozigoto , Homozigoto , Humanos , Cariótipo , Masculino , Pessoa de Meia-Idade , Anotação de Sequência Molecular , Mielofibrose Primária/diagnóstico , Mielofibrose Primária/mortalidade , Mielofibrose Primária/patologia , Prognóstico , Receptores de Trombopoetina/genética , Análise de SobrevidaRESUMO
In the last decade, several prognostic models for primary myelofibrosis (PMF) have been introduced and shown to be effective in predicting overall survival. The main objective for this study was to identify clinical and genetic markers of very long (20+ years) survival in PMF. A total of 1282 patients with PMF were considered (median age 65 years, range 19-92; 63% males); 26 (2%) patients (median age 51 years, range 28-71; 38% males) survived their disease for at least 20 years (long-lived patients) and 626 (49%) patients (median age 68 years, range 27-92; 66% males) died within 5 years of their diagnosis (short-lived patients). Multivariable logistic regression analysis identified 7 variables that were associated with survival beyond 20 years: age ≤ 70 years (P = .002); female sex (P = .03); hemoglobin level ≥ 10 g/dL for women and ≥ 11 g/dL for men (P = .03), leukocyte count ≤25 × 109 /L (P = .009), platelet count ≥100 × 109 /L (P = .002), circulating blasts <2% (P = .03) and absence of constitutional symptoms (P = .04). Five-year mortality was independently predicted by high-molecular risk mutations (P < .001); unfavorable or very high risk karyotype (P < .001); absence of type 1/like CALR mutation (P < .001); age > 70 years (P < .001); constitutional symptoms (P < .001); hemoglobin level < 10 g/dL for women and < 11 g/dL for men (P < .001); leukocyte count >25 × 109 /L (P = .004); and circulating blasts ≥2% (P = .001). This study suggests that genetic risk factors in PMF are associated with early mortality while survival beyond 20 years could be predicted by easily accessible clinical variables, including age, sex, blood counts, and symptoms.