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2.
Cancers (Basel) ; 16(8)2024 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-38672645

RESUMO

Myelodysplastic syndromes/neoplasms (MDSs) encompass a range of hematopoietic malignancies, commonly affecting elderly individuals. Molecular alterations in the hematopoietic stem cell compartment drive disease pathogenesis. Recent advancements in genomic profiling have provided valuable insights into the biological underpinnings of MDSs and have expanded therapeutic options, particularly for specific molecularly defined subgroups. This review highlights the diagnostic principles, classification updates, prognostic stratification systems, and novel treatments, which could inform future clinical trials and enhance the management of adult MDS patients, particularly for specific molecularly defined subgroups.

5.
Chemotherapy ; 67(2): 91-95, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34872098

RESUMO

BACKGROUND: Antibody response following SARS-CoV-2 vaccination is somewhat defective in chronic lymphocytic leukemia (CLL). Moreover, the correlation between serologic response and status of cellular immunity has been poorly studied. OBJECTIVE: This study was undertaken to assess humoral immune and cellular responses to the BNT162b2 messenger RNA (mRNA) COVID-19 vaccination in CLL. METHODS: The presence of the spike antibodies was assessed at a median time of 14 days from the second vaccine dose of SARS-CoV-2 in 70 CLL patients followed up at a single institution. RESULTS: The antibody response rate (RR) in CLL patients was 58.5%, compared to 100% of 57 healthy controls of the same sex and age (p < 0.0001). Treatment-naïve patients and those in sustained clinical remission after therapy had the highest RR (87.0% and 87.7%, respectively). In contrast, patients on therapy with a pathway inhibitor as monotherapy and those treated with an association of anti-CD20 antibody were unlikely to respond to the SARS-CoV-2 vaccine (52% and 10%, respectively). In multivariate analysis, early Rai stage (OR, 0.19 [0.05-0.79]; p = 0.02) and no previous therapy (OR, 0.06 [0.02-0.27]; p < 0.0001) were found to be independent predictors of vaccination response. An increase in absolute NK cells (i.e., CD16/CD56 positive cells) in patients with a serological response was found following the second dose of vaccine (p = 0.02). CONCLUSIONS: These results confirm that serological response to the BNT162b2 vaccine in patients with CLL is impaired. A third boosting vaccine dosage should be considered for these patients.


Assuntos
COVID-19 , Leucemia Linfocítica Crônica de Células B , Anticorpos Antivirais , Vacina BNT162 , COVID-19/prevenção & controle , Vacinas contra COVID-19 , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , RNA Mensageiro , SARS-CoV-2
6.
Expert Opin Investig Drugs ; 30(6): 621-633, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33929928

RESUMO

Introduction: Venetoclax has emerged as a breakthrough treatment which has revolutionized the therapeutic paradigm of chronic lymphocytic leukemia (CLL). This is primarily attributed to the efficacy of venetoclax as a time-limited, chemo-free, therapy in a field dominated by targeted agents given on a continuous schedule. Furthermore, compelling clinical data support the use of venetoclax in combination with other targeted agents in the hope of preventing drug resistance due to the emergence of acquired mutations.Areas covered: This paper provides an overview of clinical results of newly approved or investigational venetoclax-based therapies for CLL. In view of current and potential roles in CLL care, the strengths and disadvantages of venetoclax-combinations are discussed. The MEDLINE database, ClinicalTrials.gov and conference proceedings were all reviewed to select the relevant literature.Expert opinion: While the advent of venetoclax-based combinations has significantly expanded the therapeutic options for patients with CLL, further research with longer follow-up is required to address remaining open questions such as (I) the role of venetoclax as fixed duration therapy(II) timing and threshold of minimal residual disease (MRD) assessment for therapy discontinuation, (III) the efficacy of novel triplet combinations with venetoclax as backbone therapy, (IV) indications for the re-initiation of therapy with venetoclax.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Sulfonamidas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Resistencia a Medicamentos Antineoplásicos , Humanos , Terapia de Alvo Molecular , Terapias em Estudo/métodos
7.
Chemotherapy ; 65(1-2): 51-53, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32570264

RESUMO

The co-occurrence of BCR-ABL1 fusion and core-binding factor (CBF) rearrangements is uncommonly reported in AML. Although CBF rearrangements carry a favorable prognosis, the coexistence of BCR-ABL1 is associated with aggressive disease suggesting a potential advantage of high-intensity chemotherapy in association with tyrosine kinase inhibitors. Herein, we describe a refractory AML patient harboring BCR-ABL1 fusion and CBFB rearrangement that was successfully treated with a combination of venetoclax and hypomethylating agent.


Assuntos
Antineoplásicos/uso terapêutico , Azacitidina/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Proteínas de Fusão bcr-abl/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Proteínas de Fusão Oncogênica/genética , Sulfonamidas/uso terapêutico , Antineoplásicos/efeitos adversos , Azacitidina/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Doenças Hematológicas/etiologia , Humanos , Cariótipo , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Sulfonamidas/efeitos adversos
8.
Curr Hematol Malig Rep ; 15(4): 343-349, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32500413

RESUMO

PURPOSE OF REVIEW: The treatment landscape for chronic lymphocytic leukaemia (CLL) is rapidly evolving, with several targeted agents recently approved. These compounds have dramatically changed the natural history of the disease. RECENT FINDINGS: However, with the array of effective therapies commercially available, the challenge is to define tailored treatment strategies able to realize a balance between treatment efficacy and toxicity or tolerance. New algorithms of treatment are being developed, and it appears that minimal residual disease (MRD) directed therapy will become the norm in the future. Clinical trials are looking at various combinations of novel therapies given with a defined, fixed-period of treatment based on MRD analysis. This approach enables patients to have a period of treatment-free remission instead of continuous therapy. In this review, we summarize this evolution of targeted therapies in CLL.


Assuntos
Adenina/análogos & derivados , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Terapia de Alvo Molecular/tendências , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Adenina/efeitos adversos , Adenina/uso terapêutico , Antineoplásicos/efeitos adversos , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/mortalidade , Terapia de Alvo Molecular/efeitos adversos , Terapia de Alvo Molecular/mortalidade , Neoplasia Residual , Piperidinas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Transdução de Sinais/efeitos dos fármacos , Resultado do Tratamento
9.
Expert Opin Emerg Drugs ; 25(1): 25-35, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31996046

RESUMO

Introduction: In the last few years, the expansion of therapy with pathway inhibitors has revolutionized the treatment landscape of chronic lymphocytic leukemia (CLL). As a matter of fact, ibrutinib, the first-in-class Bruton tyrosine kinase (BTK) inhibitor, became a milestone in the treatment of both naïve or relapsed/refractory CLL patients. Most patients treated with such an agent achieve durable clinical response; however, a deeper response is rarely reached and continuous treatment is required. Since ibrutinib-resistant CLL clones can develop in about 20% of patients and toxicities, leading to drug discontinuation, occur in about 30% of patients treated with ibrutinib, several new BTK inhibitors have been developed in order to lower off-target effects and overcome ibrutinib resistance.Areas covered: In this review, we summarize the main English publications exploring efficacy and side effects of first and next-generation BTK inhibitors. Results of clinical trials evaluating these novel agents are presented and critically discussed.Expert opinion: Efforts in the development of highly specific second-generation BTK inhibitors and combination strategies provide challenging options to overcome limitations of therapy with ibrutinib. It is also crucial to identify additional risk factors and to understand disease biology underlying clonal evolution of CLL in the context of novel agents.


Assuntos
Adenina/análogos & derivados , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Adenina/efeitos adversos , Adenina/uso terapêutico , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Humanos , Leucemia Linfocítica Crônica de Células B/enzimologia , Estudos Multicêntricos como Assunto , Piperidinas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos
12.
Haematologica ; 104(2): 312-318, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30190342

RESUMO

To shed light onto the molecular basis of Philadelphia chromosome-positive acute lymphoblastic leukemia and to investigate the prognostic role of additional genomic lesions, we analyzed copy number aberrations using the Cytoscan HD Array in 116 newly diagnosed adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia enrolled in four different GIMEMA protocols, all based on a chemotherapy-free induction strategy. This analysis showed that patients with Philadelphia chromosome-positive acute lymphoblastic leukemia carry an average of 7.8 lesions/case, with deletions outnumbering gains (88% versus 12%). The most common deletions were those targeting IKZF1, PAX5 and CDKN2A/B, which were detected in 84%, 36% and 32% of cases, respectively. Patients carrying simultaneous deletions of IKZF1 plus CDKN2A/B and/or PAX5 had a significantly lower disease-free survival rate (24.9% versus 43.3%; P=0.026). The only IKZF1 isoform affecting prognosis was the dominant negative one (P=0.003). Analysis of copy number aberrations showed that 18% of patients harbored MEF2C deletions, which were of two types, differing in size: the longer deletions were associated with the achievement of a complete molecular remission (P=0.05) and had a favorable impact on disease-free survival (64.3% versus 32.1% at 36 months; P=0.031). These findings retained statistical significance also in multivariate analysis (P=0.057). KRAS deletions, detected in 6% of cases, were associated with the achievement of a complete molecular remission (P=0.009). These results indicate that in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia a detailed evaluation of additional deletions - including CDKN2A/B, PAX5, IKZF1, MEF2C and KRAS - has prognostic implications and should be incorporated in the design of more personalized treatment strategies.


Assuntos
Predisposição Genética para Doença , Variação Genética , Genômica , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Variações do Número de Cópias de DNA , Feminino , Estudos de Associação Genética , Genômica/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico , Análise de Sobrevida , Adulto Jovem
13.
Int J Mol Sci ; 19(8)2018 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-30110936

RESUMO

The mammalian target of rapamycin (mTOR) is a central processor of intra- and extracellular signals, regulating many fundamental cellular processes such as metabolism, growth, proliferation, and survival. Strong evidences have indicated that mTOR dysregulation is deeply implicated in leukemogenesis. This has led to growing interest in the development of modulators of its activity for leukemia treatment. This review intends to provide an outline of the principal biological and molecular functions of mTOR. We summarize the current understanding of how mTOR interacts with microRNAs, with components of cell metabolism, and with controllers of apoptotic machinery. Lastly, from a clinical/translational perspective, we recapitulate the therapeutic results in leukemia, obtained by using mTOR inhibitors as single agents and in combination with other compounds.


Assuntos
Transformação Celular Neoplásica/metabolismo , Leucemia/enzimologia , Proteínas de Neoplasias/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Apoptose/efeitos dos fármacos , Transformação Celular Neoplásica/patologia , Humanos , Leucemia/tratamento farmacológico , MicroRNAs/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , RNA Neoplásico/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores
14.
Br J Haematol ; 181(5): 642-652, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29675955

RESUMO

BCR/ABL1-like acute lymphoblastic leukaemia (ALL) is a subgroup of B-lineage acute lymphoblastic leukaemia that occurs within cases without recurrent molecular rearrangements. Gene expression profiling (GEP) can identify these cases but it is expensive and not widely available. Using GEP, we identified 10 genes specifically overexpressed by BCR/ABL1-like ALL cases and used their expression values - assessed by quantitative real time-polymerase chain reaction (Q-RT-PCR) in 26 BCR/ABL1-like and 26 non-BCR/ABL1-like cases to build a statistical "BCR/ABL1-like predictor", for the identification of BCR/ABL1-like cases. By screening 142 B-lineage ALL patients with the "BCR/ABL1-like predictor", we identified 28/142 BCR/ABL1-like patients (19·7%). Overall, BCR/ABL1-like cases were enriched in JAK/STAT mutations (P < 0·001), IKZF1 deletions (P < 0·001) and rearrangements involving cytokine receptors and tyrosine kinases (P = 0·001), thus corroborating the validity of the prediction. Clinically, the BCR/ABL1-like cases identified by the BCR/ABL1-like predictor achieved a lower rate of complete remission (P = 0·014) and a worse event-free survival (P = 0·0009) compared to non-BCR/ABL1-like ALL. Consistently, primary cells from BCR/ABL1-like cases responded in vitro to ponatinib. We propose a simple tool based on Q-RT-PCR and a statistical model that is capable of easily, quickly and reliably identifying BCR/ABL1-like ALL cases at diagnosis.


Assuntos
Proteínas de Fusão bcr-abl , Regulação Leucêmica da Expressão Gênica , Modelos Biológicos , Leucemia-Linfoma Linfoblástico de Células Precursoras , Reação em Cadeia da Polimerase em Tempo Real , Adolescente , Adulto , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Proteínas de Fusão bcr-abl/biossíntese , Proteínas de Fusão bcr-abl/genética , Humanos , Lactente , Recém-Nascido , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Valor Preditivo dos Testes , Taxa de Sobrevida
16.
Br J Haematol ; 178(4): 583-587, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28439887

RESUMO

Copy number aberrations (CNAs) represent cooperating events in B-lineage acute lymphoblastic leukaemia (B-ALL); however, their clinical relevance across different age cohorts is unclear. We analysed the recurrent CNAs in 157 age-stratified B-ALL negative cases for recurrent rearrangements (B-NEG ALL), and their association with patients' clinico-biological features. We found that: (i) CDKN2A/RB1-deleted and EBF1-deleted adults had a shorter disease-free survival than those with wild-type, (ii) among the unfavourable markers, CDKN2A/RB1 deletions and K/NRAS mutations retained their impact in multivariate analysis, encouraging the evaluation of CDKN2A/RB1 deletions and RAS mutations in the diagnostic/prognostic workflow to refine ALL risk assessment.


Assuntos
Variações do Número de Cópias de DNA/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Adolescente , Adulto , Fatores Etários , Idoso , Criança , DNA de Neoplasias/genética , Feminino , GTP Fosfo-Hidrolases/genética , Deleção de Genes , Genes p16 , Marcadores Genéticos/genética , Humanos , Lactente , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Mutação , Proteínas de Neoplasias/genética , Prognóstico , Proteínas de Ligação a Retinoblastoma/genética , Análise de Sobrevida , Ubiquitina-Proteína Ligases/genética , Adulto Jovem
17.
Am Soc Clin Oncol Educ Book ; 35: e314-22, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27249738

RESUMO

Acute lymphoblastic leukemia (ALL) remains an important cause of morbidity in children and adults. In this article, we highlight advances in the genetics and therapy of three key subtypes of ALL: T-cell ALL, BCR-ABL1 (Philadelphia [Ph] chromosone-positive), and Ph-like ALL. T-ALL is an aggressive disease that accounts for about 15% and 25% of ALL among pediatric and adult cohorts, respectively, and exhibits a multistep nature of cancer initiation and progression. The integration of cytogenetics, molecular biology, and immunophenotype analyses has led to the identification of defined T-ALL subgroups, such as early T-cell precursor ALL and novel lesions with a prognostic role, for which specific inhibitors are being developed. Ph-positive ALL was historically regarded as a subtype of ALL with a poor prognosis, and allogeneic stem cell transplant was recommended for all patients who could undergo this procedure. The deep complete responses seen with combination tyrosine kinase inhibitors (TKIs) and chemotherapy in Ph-positive ALL, and the reports of long-term survival among some patients not undergoing allogeneic stem cell transplant, has raised the question of whether there is a subset of patients who could be cured without this intervention. Ph-like ALL is a subtype of B-progenitor ALL common among older children and adults and associated with a diverse range of genetic alterations that activate kinase signaling. Ph-like ALL is also associated with poor outcome, for which precision medicine trials identifying kinase alterations and testing TKI therapy are being developed.


Assuntos
Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Criança , Transplante de Células-Tronco Hematopoéticas , Humanos , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Indução de Remissão
18.
Haematologica ; 101(8): 951-8, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27151989

RESUMO

Recurrent deletions of the long arm of chromosome 5 were detected in 23/200 cases of T-cell acute lymphoblastic leukemia. Genomic studies identified two types of deletions: interstitial and terminal. Interstitial 5q deletions, found in five cases, were present in both adults and children with a female predominance (chi-square, P=0.012). Interestingly, these cases resembled immature/early T-cell precursor acute lymphoblastic leukemia showing significant down-regulation of five out of the ten top differentially expressed genes in this leukemia group, including TCF7 which maps within the 5q31 common deleted region. Mutations of genes known to be associated with immature/early T-cell precursor acute lymphoblastic leukemia, i.e. WT1, ETV6, JAK1, JAK3, and RUNX1, were present, while CDKN2A/B deletions/mutations were never detected. All patients had relapsed/resistant disease and blasts showed an early differentiation arrest with expression of myeloid markers. Terminal 5q deletions, found in 18 of patients, were more prevalent in adults (chi-square, P=0.010) and defined a subgroup of HOXA-positive T-cell acute lymphoblastic leukemia characterized by 130 up- and 197 down-regulated genes. Down-regulated genes included TRIM41, ZFP62, MAPK9, MGAT1, and CNOT6, all mapping within the 1.4 Mb common deleted region at 5q35.3. Of interest, besides CNOT6 down-regulation, these cases also showed low BTG1 expression and a high incidence of CNOT3 mutations, suggesting that the CCR4-NOT complex plays a crucial role in the pathogenesis of HOXA-positive T-cell acute lymphoblastic leukemia with terminal 5q deletions. In conclusion, interstitial and terminal 5q deletions are recurrent genomic losses identifying distinct subtypes of T-cell acute lymphoblastic leukemia.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 5 , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Adolescente , Adulto , Biomarcadores , Criança , Estudos de Coortes , Feminino , Perfilação da Expressão Gênica , Estudos de Associação Genética , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Fenótipo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Adulto Jovem
19.
Haematologica ; 101(8): 941-50, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27151993

RESUMO

Despite therapeutic improvements, a sizable number of patients with T-cell acute lymphoblastic leukemia still have a poor outcome. To unravel the genomic background associated with refractoriness, we evaluated the transcriptome of 19 cases of refractory/early relapsed T-cell acute lymphoblastic leukemia (discovery cohort) by performing RNA-sequencing on diagnostic material. The incidence and prognostic impact of the most frequently mutated pathways were validated by Sanger sequencing on genomic DNA from diagnostic samples of an independent cohort of 49 cases (validation cohort), including refractory, relapsed and responsive cases. Combined gene expression and fusion transcript analyses in the discovery cohort revealed the presence of known oncogenes and identified novel rearrangements inducing overexpression, as well as inactivation of tumor suppressor genes. Mutation analysis identified JAK/STAT and RAS/PTEN as the most commonly disrupted pathways in patients with chemorefractory disease or early relapse, frequently in association with NOTCH1/FBXW7 mutations. The analysis on the validation cohort documented a significantly higher risk of relapse, inferior overall survival, disease-free survival and event-free survival in patients with JAK/STAT or RAS/PTEN alterations. Conversely, a significantly better survival was observed in patients harboring only NOTCH1/FBXW7 mutations: this favorable prognostic effect was abrogated by the presence of concomitant mutations. Preliminary in vitro assays on primary cells demonstrated sensitivity to specific inhibitors. These data document the negative prognostic impact of JAK/STAT and RAS/PTEN mutations in T-cell acute lymphoblastic leukemia and suggest the potential clinical application of JAK and PI3K/mTOR inhibitors in patients harboring mutations in these pathways.


Assuntos
Variação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Análise de Sequência de RNA , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteínas de Ciclo Celular/metabolismo , Criança , Análise por Conglomerados , Estudos de Coortes , Resistencia a Medicamentos Antineoplásicos , Proteínas F-Box/metabolismo , Proteína 7 com Repetições F-Box-WD , Feminino , Perfilação da Expressão Gênica , Humanos , Janus Quinases/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas de Fusão Oncogênica/genética , PTEN Fosfo-Hidrolase/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Prognóstico , Receptor Notch1/genética , Receptor Notch1/metabolismo , Recidiva , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Análise de Sobrevida , Resultado do Tratamento , Ubiquitina-Proteína Ligases/metabolismo , Adulto Jovem , Proteínas ras/metabolismo
20.
Oncotarget ; 7(12): 13886-901, 2016 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-26883104

RESUMO

To shed light into the molecular bases of B-lineage acute lymphoblastic leukemia lacking known fusion transcripts, i.e. BCR-ABL1, ETV6-RUNX1, E2A-PBX1, and MLL rearrangements (B-NEG ALL) and the differences between children, adolescents/young adults (AYA) and adults, we analyzed 168 B-NEG ALLs by genome-wide technologies. This approach showed that B-NEG cases carry 10.5 mutations and 9.1 copy-number aberrations/sample. The most frequently mutated druggable pathways were those pertaining to RAS/RTK (26.8%) and JAK/STAT (12.5%) signaling. In particular, FLT3 and JAK/STAT mutations were detected mainly in AYA and adults, while KRAS and NRAS mutations were more frequent in children. RAS/RTK mutations negatively affected the outcome of AYA and adults, but not that of children. Furthermore, adult B-NEG ALL carrying JAK/STAT mutations had a shorter survival. In vitro experiments showed that FLT3 inhibitors reduced significantly the proliferation of FLT3-mutated primary B-NEG ALL cells. Likewise, PI3K/mTOR inhibitors reduced the proliferation of primary cells harboring RAS and IL7R mutations. These results refine the genetic landscape of B-NEG ALL and suggest that the different distribution of lesions and their prognostic impact might sustain the diverse outcome between children, adults and partly AYA - whose genomic scenario is similar to adults - and open the way to targeted therapeutic strategies.


Assuntos
Biomarcadores Tumorais/genética , Mutação , Proteínas de Fusão Oncogênica/genética , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Adolescente , Adulto , Idoso , Linhagem da Célula , Criança , Pré-Escolar , Feminino , Seguimentos , Perfilação da Expressão Gênica , Regulação Leucêmica da Expressão Gênica , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Prognóstico , Taxa de Sobrevida , Adulto Jovem
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