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1.
Nature ; 553(7689): 511-514, 2018 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-29342136

RESUMO

Relapsed acute lymphoblastic leukaemia (ALL) is associated with resistance to chemotherapy and poor prognosis. Gain-of-function mutations in the 5'-nucleotidase, cytosolic II (NT5C2) gene induce resistance to 6-mercaptopurine and are selectively present in relapsed ALL. Yet, the mechanisms involved in NT5C2 mutation-driven clonal evolution during the initiation of leukaemia, disease progression and relapse remain unknown. Here we use a conditional-and-inducible leukaemia model to demonstrate that expression of NT5C2(R367Q), a highly prevalent relapsed-ALL NT5C2 mutation, induces resistance to chemotherapy with 6-mercaptopurine at the cost of impaired leukaemia cell growth and leukaemia-initiating cell activity. The loss-of-fitness phenotype of NT5C2+/R367Q mutant cells is associated with excess export of purines to the extracellular space and depletion of the intracellular purine-nucleotide pool. Consequently, blocking guanosine synthesis by inhibition of inosine-5'-monophosphate dehydrogenase (IMPDH) induced increased cytotoxicity against NT5C2-mutant leukaemia lymphoblasts. These results identify the fitness cost of NT5C2 mutation and resistance to chemotherapy as key evolutionary drivers that shape clonal evolution in relapsed ALL and support a role for IMPDH inhibition in the treatment of ALL.


Assuntos
5'-Nucleotidase/genética , 5'-Nucleotidase/metabolismo , Evolução Clonal , Resistencia a Medicamentos Antineoplásicos/genética , Mutação/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Animais , Proliferação de Células , Modelos Animais de Doenças , Feminino , Mutação com Ganho de Função/genética , Guanosina/biossíntese , Células HEK293 , Humanos , IMP Desidrogenase/antagonistas & inibidores , IMP Desidrogenase/metabolismo , Masculino , Mercaptopurina/farmacologia , Mercaptopurina/uso terapêutico , Camundongos , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Purinas/metabolismo , Receptor Notch1/metabolismo , Recidiva , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Skeletal Radiol ; 53(4): 817-820, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37672091

RESUMO

A 5-month-old infant with bone findings on x-ray presented an apparent contradiction including findings of both diffusely dense bones and rickets in the context of a history and laboratory investigation that suggested leukemia. Next generation gene panel sequencing revealed a TCIRG1 mutation which is consistent with autosomal recessive osteopetrosis. The paradoxical x-ray findings underscore a recently elucidated mechanism for the pathogenesis of a TCIRG mutation. This case highlights the importance of recognizing this radiographic, seeming contradictory, association in the context of a confusing clinical presentation. Failure to recognize this pattern promptly may lead to a delay in diagnosis, thus potentially permanent organ failure.


Assuntos
Osteopetrose , Raquitismo , ATPases Vacuolares Próton-Translocadoras , Lactente , Humanos , Osteopetrose/diagnóstico por imagem , Osteopetrose/genética , Osteopetrose/patologia , Raquitismo/diagnóstico por imagem , Radiografia , Mutação , ATPases Vacuolares Próton-Translocadoras/genética
3.
Pediatr Hematol Oncol ; 41(5): 376-381, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38454568

RESUMO

Due to an evidence gap, the emetogenicity of intravenous (IV) pegaspargase was unable to be included in the clinical practice guideline classifying chemotherapy emetogenicity in pediatric patients. This single-center, retrospective chart review describes the proportion of pediatric patients who did not vomit during the acute phase (complete response; CR) after receiving IV pegaspargase and provides an emetogenicity classification using a preexisting framework. Of 44 patients who received IV pegaspargase between 2011 and 2020, 13 received a serotonin receptor antagonist plus dexamethasone or palonosetron alone and all experienced a CR. We, therefore, recommend classifying IV pegaspargase as moderately emetogenic.


Assuntos
Asparaginase , Polietilenoglicóis , Vômito , Humanos , Estudos Retrospectivos , Criança , Adolescente , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/uso terapêutico , Masculino , Feminino , Asparaginase/administração & dosagem , Asparaginase/efeitos adversos , Vômito/induzido quimicamente , Pré-Escolar , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Dexametasona/uso terapêutico , Administração Intravenosa , Antieméticos/administração & dosagem , Antieméticos/uso terapêutico , Lactente
4.
Support Care Cancer ; 31(2): 109, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36625831

RESUMO

PURPOSE: Neurocognitive impairment is frequently observed among survivors of childhood acute lymphoblastic leukemia (ALL) within the domains of attention, working memory, processing speed, executive functioning, and learning and memory. However, few studies have characterized the trajectory of treatment-induced changes in neurocognitive function beginning in the first months of treatment, to test whether early changes predict impairment among survivors. If correct, we hypothesize that those children who are most susceptible to early impairment would be ideal subjects for clinical trials testing interventions designed to protect against treatment-related neurocognitive decline. METHODS: In this pilot study, we prospectively assessed neurocognitive functioning (attention, working memory, executive function, visual learning, and processing speed), using the Cogstate computerized battery at six time points during the 2 years of chemotherapy treatment and 1-year post-treatment (Dana-Farber Cancer Institute ALL Consortium protocol 11-001; NCT01574274). RESULTS: Forty-three patients with ALL consented to serial neurocognitive testing. Of the 31 participants who remained on study through the final time point, 1 year after completion of chemotherapy, 28 (90%) completed at least five of six planned Cogstate testing time points. Performance and completion checks indicated a high tolerability (≥ 88%) for all subtests. One year after completion of treatment, 10 of 29 patients (34%) exhibited neurocognitive function more than 2 standard deviations below age-matched norms on one or more Cogstate subtests. CONCLUSIONS: Serial collection of neurocognitive data (within a month of diagnosis with ALL, during therapy, and 1-year post-treatment) is feasible and can be informative for evaluating treatment-related neurocognitive impairment.


Assuntos
Função Executiva , Leucemia , Criança , Humanos , Estudos de Viabilidade , Memória de Curto Prazo , Testes Neuropsicológicos , Projetos Piloto , Estudos Prospectivos
5.
Haematologica ; 107(10): 2295-2303, 2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-35112552

RESUMO

Phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling is commonly dysregulated in acute lymphoblastic leukemia (ALL). The TACL2014-001 phase I trial of the mTOR inhibitor temsirolimus in combination with cyclophosphamide and etoposide was performed in children and adolescents with relapsed/refractory ALL. Temsirolimus was administered intravenously (IV) on days 1 and 8 with cyclophosphamide 440 mg/m2 and etoposide 100 mg/m2 IV daily on days 1-5. The starting dose of temsirolimus was 7.5 mg/m2 (DL1) with escalation to 10 mg/m2 (DL2), 15 mg/m2 (DL3), and 25 mg/m2 (DL4). PI3K/mTOR pathway inhibition was measured by phosphoflow cytometry analysis of peripheral blood specimens from treated patients. Sixteen heavily-pretreated patients were enrolled with 15 evaluable for toxicity. One dose-limiting toxicity of grade 4 pleural and pericardial effusions occurred in a patient treated at DL3. Additional dose-limiting toxicities were not seen in the DL3 expansion or DL4 cohort. Grade 3/4 non-hematologic toxicities occurring in three or more patients included febrile neutropenia, elevated alanine aminotransferase, hypokalemia, mucositis, and tumor lysis syndrome and occurred across all doses. Response and complete were observed at all dose levels with a 47% overall response rate and 27% complete response rate. Pharmacodynamic correlative studies demonstrated dose-dependent inhibition of PI3K/mTOR pathway phosphoproteins in all studied patients. Temsirolimus at doses up to 25 mg/m2 with cyclophosphamide and etoposide had an acceptable safety profile in children with relapsed/refractory ALL. Pharmacodynamic mTOR target inhibition was achieved and appeared to correlate with temsirolimus dose. Future testing of next-generation PI3K/mTOR pathway inhibitors with chemotherapy may be warranted to increase response rates in children with relapsed/refractory ALL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Alanina Transaminase/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Ciclofosfamida/uso terapêutico , Etoposídeo , Humanos , Inibidores de MTOR , Fosfatidilinositol 3-Quinases , Inibidores de Fosfoinositídeo-3 Quinase , Fosfoproteínas , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Sirolimo/análogos & derivados , Serina-Treonina Quinases TOR
6.
Nat Chem Biol ; 16(12): 1403-1410, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32868895

RESUMO

The nuclear receptor-binding SET domain (NSD) family of histone methyltransferases is associated with various malignancies, including aggressive acute leukemia with NUP98-NSD1 translocation. While NSD proteins represent attractive drug targets, their catalytic SET domains exist in autoinhibited conformation, presenting notable challenges for inhibitor development. Here, we employed a fragment-based screening strategy followed by chemical optimization, which resulted in the development of the first-in-class irreversible small-molecule inhibitors of the nuclear receptor-binding SET domain protein 1 (NSD1) SET domain. The crystal structure of NSD1 in complex with covalently bound ligand reveals a conformational change in the autoinhibitory loop of the SET domain and formation of a channel-like pocket suitable for targeting with small molecules. Our covalent lead-compound BT5-demonstrates on-target activity in NUP98-NSD1 leukemia cells, including inhibition of histone H3 lysine 36 dimethylation and downregulation of target genes, and impaired colony formation in an NUP98-NSD1 patient sample. This study will facilitate the development of the next generation of potent and selective inhibitors of the NSD histone methyltransferases.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Regulação Leucêmica da Expressão Gênica , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Leucócitos/efeitos dos fármacos , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Proteínas de Fusão Oncogênica/antagonistas & inibidores , Antineoplásicos/síntese química , Sítios de Ligação , Inibidores Enzimáticos/síntese química , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Cinética , Leucemia/tratamento farmacológico , Leucemia/enzimologia , Leucemia/genética , Leucemia/patologia , Leucócitos/enzimologia , Leucócitos/patologia , Modelos Moleculares , Proteína Meis1/genética , Proteína Meis1/metabolismo , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Transdução de Sinais , Especificidade por Substrato , Células Tumorais Cultivadas
7.
Pediatr Blood Cancer ; 68(1): e28719, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33026184

RESUMO

BACKGROUND/OBJECTIVES: While outcomes for pediatric T-cell acute lymphoblastic leukemia (T-ALL) are favorable, there are few widely accepted prognostic factors, limiting the ability to risk stratify therapy. DESIGN/METHODS: Dana-Farber Cancer Institute (DFCI) Protocols 05-001 and 11-001 enrolled pediatric patients with newly diagnosed B- or T-ALL from 2005 to 2011 and from 2012 to 2015, respectively. Protocol therapy was nearly identical for patients with T-ALL (N = 123), who were all initially assigned to the high-risk arm. End-induction minimal residual disease (MRD) was assessed by reverse transcription polymerase chain reaction (RT-PCR) or next-generation sequencing (NGS), but was not used to modify postinduction therapy. Early T-cell precursor (ETP) status was determined by flow cytometry. Cases with sufficient diagnostic DNA were retrospectively evaluated by targeted NGS of known genetic drivers of T-ALL, including Notch, PI3K, and Ras pathway genes. RESULTS: The 5-year event-free survival (EFS) and overall survival (OS) for patients with T-ALL was 81% (95% CI, 73-87%) and 90% (95% CI, 83-94%), respectively. ETP phenotype was associated with failure to achieve complete remission, but not with inferior OS. Low end-induction MRD (<10-4 ) was associated with superior disease-free survival (DFS). Pathogenic mutations of the PI3K pathway were mutually exclusive of ETP phenotype and were associated with inferior 5-year DFS and OS. CONCLUSIONS: Together, our findings demonstrate that ETP phenotype, end-induction MRD, and PI3K pathway mutation status are prognostically relevant in pediatric T-ALL and should be considered for risk classification in future trials. DFCI Protocols 05-001 and 11-001 are registered at www.clinicaltrials.gov as NCT00165087 and NCT01574274, respectively.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasia Residual/patologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Ensaios Clínicos Fase III como Assunto , Feminino , Seguimentos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino , Neoplasia Residual/tratamento farmacológico , Neoplasia Residual/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Indução de Remissão , Estudos Retrospectivos , Taxa de Sobrevida , Adulto Jovem
8.
J Pediatr Hematol Oncol ; 43(7): e997-e999, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34001785

RESUMO

Vincristine, a key agent in the treatment of many pediatric malignancies, causes sensory, motor and autonomic neuropathy. We report the clinical courses of 5 patients who required cessation of vincristine after developing severe neurotoxicity during treatment for acute lymphoblastic leukemia. All 5 patients lost the ability to ambulate and 3 had additional severe neurotoxic side effects including vision loss and vocal cord dysfunction. Although prior literature reports poor outcomes for children in whom vincristine was discontinued during acute lymphoblastic leukemia therapy, all 5 patients described here achieved and have maintained complete continuous remission.


Assuntos
Antineoplásicos Fitogênicos/efeitos adversos , Síndromes Neurotóxicas/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Vincristina/efeitos adversos , Suspensão de Tratamento/estatística & dados numéricos , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Síndromes Neurotóxicas/etiologia , Prognóstico , Estudos Retrospectivos
9.
Pediatr Hematol Oncol ; 37(6): 465-474, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32338562

RESUMO

Background: Panobinostat demonstrates activity against pediatric cancers in vitro. A phase I trial in children with refractory hematologic malignancies was conducted. Study design: The trial evaluated two schedules of oral panobinostat using 3 + 3 dose escalations in 28-day cycles. For children with leukemia, panobinostat was given once daily three days a week each week at 24, 30 and 34 mg/m2/day. For children with lymphoma, panobinostat was given once daily three days a week every other week at 16, 20 and 24 mg/m2/day. Cerebrospinal fluid (CSF) from Day 29 of the first cycle, when available, was evaluated for PK. The study was registered on clinicaltrials.gov (NCT01321346) Results: Twenty-two subjects enrolled with leukemia. Five enrolled at dose level 1, 6 at dose level 2, and 11 at dose level 3. There was one dose limiting toxicity (DLT) in the leukemia arm at dose level 3 (Grade 4 hypertriglyceridemia), but no maximum tolerated dose (MTD) was identified. No subjects required removal from protocol therapy for QTc prolongation. PK studies were available in 11 subjects with similar exposure in children as in adults. Four Day 29 CSF specimens were found to have panobinostat levels below the lower limit of quantification. Five subjects with lymphoma were enrolled and received study drug, and 4 were evaluable for DLT. A DLT was reported (Grade 3 enteritis) on the lymphoma arm. Conclusions: Panobinostat was tolerated in heavily pretreated pediatric subjects. Gastrointestinal effects were observed on this study. There were no cardiac findings. There were no responses.


Assuntos
Neoplasias Hematológicas/tratamento farmacológico , Leucemia/tratamento farmacológico , Linfoma/tratamento farmacológico , Panobinostat/administração & dosagem , Administração Oral , Adulto , Criança , Feminino , Neoplasias Hematológicas/sangue , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/induzido quimicamente , Leucemia/sangue , Linfoma/sangue , Masculino , Panobinostat/efeitos adversos , Recidiva
10.
Proc Natl Acad Sci U S A ; 113(40): 11306-11311, 2016 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-27655895

RESUMO

Although multiagent combination chemotherapy is curative in a significant fraction of childhood acute lymphoblastic leukemia (ALL) patients, 20% of cases relapse and most die because of chemorefractory disease. Here we used whole-exome and whole-genome sequencing to analyze the mutational landscape at relapse in pediatric ALL cases. These analyses identified numerous relapse-associated mutated genes intertwined in chemotherapy resistance-related protein complexes. In this context, RAS-MAPK pathway-activating mutations in the neuroblastoma RAS viral oncogene homolog (NRAS), kirsten rat sarcoma viral oncogene homolog (KRAS), and protein tyrosine phosphatase, nonreceptor type 11 (PTPN11) genes were present in 24 of 55 (44%) cases in our series. Interestingly, some leukemias showed retention or emergence of RAS mutant clones at relapse, whereas in others RAS mutant clones present at diagnosis were replaced by RAS wild-type populations, supporting a role for both positive and negative selection evolutionary pressures in clonal evolution of RAS-mutant leukemia. Consistently, functional dissection of mouse and human wild-type and mutant RAS isogenic leukemia cells demonstrated induction of methotrexate resistance but also improved the response to vincristine in mutant RAS-expressing lymphoblasts. These results highlight the central role of chemotherapy-driven selection as a central mechanism of leukemia clonal evolution in relapsed ALL, and demonstrate a previously unrecognized dual role of RAS mutations as drivers of both sensitivity and resistance to chemotherapy.


Assuntos
Evolução Clonal/genética , Genes ras , Mutação/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Sequência de Bases , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Metotrexato/farmacologia , Metotrexato/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Vincristina/farmacologia , Vincristina/uso terapêutico
11.
Pediatr Blood Cancer ; 65(7): e27062, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29603593

RESUMO

BACKGROUND: We sought to determine the feasibility of co-administering everolimus with a four-drug reinduction in children and adolescents with acute lymphoblastic leukemia (ALL) experiencing a first marrow relapse. PROCEDURE: This phase I study tested everolimus with vincristine, prednisone, pegaspargase and doxorubicin in patients with marrow relapse occurring >18 months after first complete remission (CR). The primary aim was to identify the maximum tolerated dose of everolimus. Three dose levels (DLs) were tested during dose escalation (2, 3, and 5 mg/m2 /day). Additional patients were enrolled at the 3- and 5 mg/m2 /day DLs to further evaluate toxicity (dose expansion). RESULTS: Thirteen patients enrolled during dose escalation and nine during dose expansion. During dose escalation, one dose-limiting toxicity occurred (grade 4 hyperbilirubinemia) in six evaluable patients at DL3 (5 mg/m2 /day). The most common grade ≥3 adverse events were febrile neutropenia, infections, transaminitis, hyperbilirubinemia, and hypophosphatemia. Two of the 12 patients treated at DL3 developed Rothia mucilaginosa meningitis. Nineteen patients (86%) achieved a second CR (CR2). Of those, 13 (68%) had a low end-reinduction minimal residual disease (MRD) level (≤10-3 by polymerase chain reaction-based assay). The CR2 rate for patients with B-cell ALL treated at DL3 (n = 12) was 92%; 82% of these patients had low MRD. CONCLUSIONS: Everolimus combined with four-drug reinduction chemotherapy was generally well tolerated and associated with favorable rates of CR2 and low end-reinduction MRD. The recommended phase 2 dose of everolimus given in combination with a four-drug reinduction is 5 mg/m2 /day. This promising combination should be further evaluated in a larger patient cohort.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Everolimo/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Asparaginase/administração & dosagem , Asparaginase/efeitos adversos , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Everolimo/efeitos adversos , Feminino , Humanos , Lactente , Masculino , Dose Máxima Tolerável , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Indução de Remissão/métodos , Serina-Treonina Quinases TOR/antagonistas & inibidores , Vincristina/administração & dosagem , Vincristina/efeitos adversos , Adulto Jovem
12.
Pediatr Blood Cancer ; 65(10): e27256, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29878490

RESUMO

BACKGROUND: Children and adolescents with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) are reported to have increased relapse rates and therapy-related mortality (TRM). Treatment regimens for DS-ALL patients often include therapy modifications. Dana-Farber Cancer Institute (DFCI) ALL Consortium protocols have used same risk-stratified treatment for patients with and without DS. PROCEDURES: We compared clinical and outcome data of DS (n = 38) and non-DS (n = 1,248) patients enrolled on two consecutive DFCI ALL trials 00-001 (2000-2004) and 05-001 (2005-2011) with similar risk adapted therapy regardless of DS status. RESULTS: There was no difference in demographic or presenting clinical features between two groups except absence of T-cell phenotype and lower frequency of hyperdiploidy in DS-ALL group. All DS-ALL patients achieved complete remission; four relapsed and one subsequently died. There was no TRM in DS-ALL patients. DS-ALL patients had significantly higher rates of mucositis (52% vs. 12%, p < 0.001), non-CNS thrombosis (18% vs. 8%; p = 0.036), and seizure (16% vs. 5%, p = 0.010). Compared to non-DS-ALL patients, DS-ALL patients had a higher incidence of infections during all therapy phases. The 5-year event-free and overall survival rates of DS-ALL patients were similar to non-DS-ALL patients (91% [95% confidence interval (CI), 81-100] vs. 84% [95% CI, 82-86]; 97% [95% CI, 92-100] vs. 91% [95% CI, 90-93]). CONCLUSION: The low rates of relapse and TRM indicate that uniform risk-stratified therapy for DS-ALL and non-DS-ALL patients on DFCI ALL Consortium protocols was safe and effective, although the increased rate of toxicity in the DS-ALL patients highlights the importance of supportive care during therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Síndrome de Down , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Criança , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Resultado do Tratamento
13.
Proc Natl Acad Sci U S A ; 112(25): 7773-8, 2015 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-26056302

RESUMO

The transcription factor T-helper-inducing POZ/Krueppel-like factor (ThPOK, encoded by the Zbtb7b gene) plays widespread and critical roles in T-cell development, particularly as the master regulator of CD4 commitment. Here we show that mice expressing a constitutive T-cell-specific ThPOK transgene (ThPOK(const) mice) develop thymic lymphomas. These tumors resemble human T-cell acute lymphoblastic leukemia (T-ALL), in that they predominantly exhibit activating Notch1 mutations. Lymphomagenesis is prevented if thymocyte development is arrested at the DN3 stage by recombination-activating gene (RAG) deficiency, but restored by introduction of a T-cell receptor (TCR) transgene or by a single injection of anti-αßTCR antibody into ThPOK(const) RAG-deficient mice, which promotes development to the CD4(+)8(+) (DP) stage. Hence, TCR signals and/or traversal of the DN (double negative) > DP (double positive) checkpoint are required for ThPOK-mediated lymphomagenesis. These results demonstrate a novel link between ThPOK, TCR signaling, and lymphomagenesis. Finally, we present evidence that ectopic ThPOK expression gives rise to a preleukemic and self-perpetuating DN4 lymphoma precursor population. Our results collectively define a novel role for ThPOK as an oncogene and precisely map the stage in thymopoiesis susceptible to ThPOK-dependent tumor initiation.


Assuntos
Regulação da Expressão Gênica , Linfoma de Células T/patologia , Linfócitos T/citologia , Fatores de Transcrição/genética , Animais , Incidência , Linfoma de Células T/genética , Camundongos , Receptores de Antígenos de Linfócitos T/genética , Receptores Notch/metabolismo , Transdução de Sinais , Transgenes
14.
Cancer ; 123(19): 3781-3790, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-28542918

RESUMO

BACKGROUND: Pediatric oncology patients are at an increased risk of invasive bacterial infection due to immunosuppression. The risk of such infection in the absence of severe neutropenia (absolute neutrophil count ≥ 500/µL) is not well established and a validated prediction model for blood stream infection (BSI) risk offers clinical usefulness. METHODS: A 6-site retrospective external validation was conducted using a previously published risk prediction model for BSI in febrile pediatric oncology patients without severe neutropenia: the Esbenshade/Vanderbilt (EsVan) model. A reduced model (EsVan2) excluding 2 less clinically reliable variables also was created using the initial EsVan model derivative cohort, and was validated using all 5 external validation cohorts. One data set was used only in sensitivity analyses due to missing some variables. RESULTS: From the 5 primary data sets, there were a total of 1197 febrile episodes and 76 episodes of bacteremia. The overall C statistic for predicting bacteremia was 0.695, with a calibration slope of 0.50 for the original model and a calibration slope of 1.0 when recalibration was applied to the model. The model performed better in predicting high-risk bacteremia (gram-negative or Staphylococcus aureus infection) versus BSI alone, with a C statistic of 0.801 and a calibration slope of 0.65. The EsVan2 model outperformed the EsVan model across data sets with a C statistic of 0.733 for predicting BSI and a C statistic of 0.841 for high-risk BSI. CONCLUSIONS: The results of this external validation demonstrated that the EsVan and EsVan2 models are able to predict BSI across multiple performance sites and, once validated and implemented prospectively, could assist in decision making in clinical practice. Cancer 2017;123:3781-3790. © 2017 American Cancer Society.


Assuntos
Bacteriemia/diagnóstico , Neutropenia Febril/microbiologia , Hospedeiro Imunocomprometido , Modelos Estatísticos , Neoplasias , Criança , Pré-Escolar , Conjuntos de Dados como Assunto , Infecções por Bactérias Gram-Negativas/diagnóstico , Humanos , Valor Preditivo dos Testes , Estudos Retrospectivos , Risco , Infecções Estafilocócicas/diagnóstico , Staphylococcus aureus , Incerteza
15.
Pediatr Hematol Oncol ; 34(6-7): 355-364, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29190164

RESUMO

During the 2016 Therapeutic Advances for Childhood Leukemia & Lymphoma (TACL) Consortium investigators' meeting (Los Angeles, CA), a Biology Working Group was established to support the consortium's mission of developing innovative therapies for currently incurable childhood leukemias and lymphomas. The charge of the Biology Working Group was to address how TACL could advance biological investigations of pediatric relapsed/refractory hematologic malignancies while undertaking forward-looking therapeutic trials. To this end, the TACL Biology Committee was established to provide the scientific platform needed to further develop preclinical and translational studies that will advance the understanding and treatment of relapsed and refractory disease. The Biology Committee will focus on ensuring state-of-the-art studies that address biological components of early phase clinical trials, and developing a central biology bank of materials from these early phase trials for interrogations into the mechanisms of disease resistance.


Assuntos
Leucemia , Linfoma , Pesquisa Translacional Biomédica , Doença Aguda , Adolescente , Criança , Pré-Escolar , Congressos como Assunto , Feminino , Humanos , Lactente , Recém-Nascido , Leucemia/genética , Leucemia/metabolismo , Leucemia/patologia , Leucemia/terapia , Masculino , Recidiva
18.
Nat Med ; 13(10): 1203-10, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17873882

RESUMO

Gain-of-function mutations in NOTCH1 are common in T-cell lymphoblastic leukemias and lymphomas (T-ALL), making this receptor a promising target for drugs such as gamma-secretase inhibitors, which block a proteolytic cleavage required for NOTCH1 activation. However, the enthusiasm for these therapies has been tempered by tumor resistance and the paucity of information on the oncogenic programs regulated by oncogenic NOTCH1. Here we show that NOTCH1 regulates the expression of PTEN (encoding phosphatase and tensin homolog) and the activity of the phosphoinositol-3 kinase (PI3K)-AKT signaling pathway in normal and leukemic T cells. Notch signaling and the PI3K-AKT pathway synergize in vivo in a Drosophila melanogaster model of Notch-induced tumorigenesis, and mutational loss of PTEN is associated with human T-ALL resistance to pharmacological inhibition of NOTCH1. Overall, these findings identify transcriptional control of PTEN and regulation of the PI3K-AKT pathway as key elements of the leukemogenic program activated by NOTCH1 and provide the basis for the design of new therapeutic strategies for T-ALL.


Assuntos
Proteínas de Drosophila/genética , Regulação Leucêmica da Expressão Gênica/genética , Leucemia de Células T/metabolismo , PTEN Fosfo-Hidrolase/genética , Receptor Notch1/antagonistas & inibidores , Animais , Análise Mutacional de DNA , Modelos Animais de Doenças , Drosophila/genética , Drosophila/metabolismo , Proteínas de Drosophila/metabolismo , Feminino , Humanos , Leucemia de Células T/genética , Camundongos , Modelos Genéticos , Mutação , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Gravidez , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor Notch1/genética , Receptor Notch1/metabolismo , Transdução de Sinais , Transgenes
19.
Leukemia ; 38(8): 1674-1687, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38890447

RESUMO

Chromosomal translocations of the nucleoporin 98 (NUP98) gene are found in acute myeloid leukemia (AML) patients leading to very poor outcomes. The oncogenic activity of NUP98 fusion proteins is dependent on the interaction between Mixed Lineage Leukemia 1 and menin. NUP98-rearranged (NUP98-r) leukemia cells also rely on specific kinases, including CDK6 and/or FLT3, suggesting that simultaneous targeting of these kinases and menin could overcome limited sensitivity to single agents. Here, we found that combinations of menin inhibitor, MI-3454, with kinase inhibitors targeting either CDK6 (Palbociclib) or FLT3 (Gilteritinib) strongly enhance the anti-leukemic effect of menin inhibition in NUP98-r leukemia models. We found strong synergistic effects of both combinations on cell growth, colony formation and differentiation in patient samples with NUP98 translocations. These combinations also markedly augmented anti-leukemic efficacy of menin inhibitor in Patient Derived Xenograft models of NUP98-r leukemia. Despite inhibiting two unrelated kinases, when Palbociclib or Gilteritinib were combined with the menin inhibitor, they affected similar pathways relevant to leukemogenesis, including cell cycle regulation, cell proliferation and differentiation. This study provides strong rationale for clinical translation of the combination of menin and kinase inhibitors as novel treatments for NUP98-r leukemia, supporting the unexplored combinations of epigenetic drugs with kinase inhibitors.


Assuntos
Complexo de Proteínas Formadoras de Poros Nucleares , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas , Translocação Genética , Humanos , Animais , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Piridinas/farmacologia , Piridinas/uso terapêutico , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Linhagem Celular Tumoral , Compostos de Anilina , Pirazinas
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