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1.
Sci Rep ; 11(1): 2801, 2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33531590

RESUMO

Juvenile myelomonocytic leukemia (JMML) treatment primarily relies on hematopoietic stem cell transplantation and results in long-term overall survival of 50-60%, demonstrating a need to develop novel treatments. Dysregulation of the non-coding RNA transcriptome has been demonstrated before in this rare and unique disorder of early childhood. In this study, we investigated the therapeutic potential of targeting overexpressed long non-coding RNAs (lncRNAs) in JMML. Total RNA sequencing of bone marrow and peripheral blood mononuclear cell preparations from 19 untreated JMML patients and three healthy children revealed 185 differentially expressed lncRNA genes (131 up- and 54 downregulated). LNA GapmeRs were designed for 10 overexpressed and validated lncRNAs. Molecular knockdown (≥ 70% compared to mock control) after 24 h of incubation was observed with two or more independent GapmeRs in 6 of them. For three lncRNAs (lnc-THADA-4, lnc-ACOT9-1 and NRIR) knockdown resulted in a significant decrease of cell viability after 72 h of incubation in primary cultures of JMML mononuclear cells, respectively. Importantly, the extent of cellular damage correlated with the expression level of the lncRNA of interest. In conclusion, we demonstrated in primary JMML cell cultures that knockdown of overexpressed lncRNAs such as lnc-THADA-4, lnc-ACOT9-1 and NRIR may be a feasible therapeutic strategy.

2.
Blood ; 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33171484

RESUMO

Ovarian tissue cryopreservation (OTC) is offered to women treated for acute leukemia to preserve their fertility before hematopoietic stem cell transplantation. The risk of leukemic infiltration in ovarian samples harvested before administration of chemotherapy limits ovarian tissue transplantations. We assessed the minimal residual disease (MRD) by sensitive quantitative polymerase chain reaction in cryopreserved ovarian cortex and medulla samples harvested from 30 patients in complete remission of acute leukemia, including 60 % with negative bone marrow MRD at the time of OTC. Ovarian MRD was undetectable in 21 patients (70%), detectable below 10-4 in 8 patients (27%) and between 10-3 and 10-4 in 1 patient (3%). Twenty patients (67%) had concordant MRD between bone marrow and ovarian samples. Interestingly 4 patients had positive MRD in ovarian samples while undetectable in bone marrow. Our results underline the importance of reaching the best control of the disease with undetectable or low MRD levels before OTC to minimize the risk of ovarian leukemic infiltration. The discordant results between ovarian samples and bone marrow require to test the more ovarian samples available before considering ovarian tissue transplantation.

4.
Leukemia ; 34(6): 1658-1668, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31776464

RESUMO

Juvenile myelomonocytic leukemia (JMML) is a rare aggressive myelodysplastic/myeloproliferative neoplasm of early childhood, initiated by RAS-activating mutations. Genomic analyses have recently described JMML mutational landscape; however, the nature of JMML-propagating cells (JMML-PCs) and the clonal architecture of the disease remained until now elusive. Combining genomic (exome, RNA-seq), Colony forming assay and xenograft studies, we detect the presence of JMML-PCs that faithfully reproduce JMML features including the complex/nonlinear organization of dominant/minor clones, both at diagnosis and relapse. Further integrated analysis also reveals that although the mutations are acquired in hematopoietic stem cells, JMML-PCs are not always restricted to this compartment, highlighting the heterogeneity of the disease during the initiation steps. We show that the hematopoietic stem/progenitor cell phenotype is globally maintained in JMML despite overexpression of CD90/THY-1 in a subset of patients. This study shed new lights into the ontogeny of JMML, and the identity of JMML-PCs, and provides robust models to monitor the disease and test novel therapeutic approaches.


Assuntos
Células-Tronco Hematopoéticas/patologia , Leucemia Mielomonocítica Juvenil/patologia , Células-Tronco Neoplásicas/patologia , Adolescente , Animais , Criança , Pré-Escolar , Feminino , Xenoenxertos , Humanos , Lactente , Leucemia Mielomonocítica Juvenil/genética , Masculino , Camundongos , Mutação
5.
Haematologica ; 103(8): 1278-1287, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29724903

RESUMO

Heterozygous germline GATA2 mutations strongly predispose to leukemia, immunodeficiency, and/or lymphoedema. We describe a series of 79 patients (53 families) diagnosed since 2011, made up of all patients in France and Belgium, with a follow up of 2249 patients/years. Median age at first clinical symptoms was 18.6 years (range, 0-61 years). Severe infectious diseases (mycobacteria, fungus, and human papilloma virus) and hematologic malignancies were the most common first manifestations. The probability of remaining symptom-free was 8% at 40 years old. Among the 53 probands, 24 had missense mutations including 4 recurrent alleles, 21 had nonsense or frameshift mutations, 4 had a whole-gene deletion, 2 had splice defects, and 2 patients had complex mutations. There were significantly more cases of leukemia in patients with missense mutations (n=14 of 34) than in patients with nonsense or frameshift mutations (n=2 of 28). We also identify new features of the disease: acute lymphoblastic leukemia, juvenile myelomonocytic leukemia, fatal progressive multifocal leukoencephalopathy related to the JC virus, and immune/inflammatory diseases. A revised International Prognostic Scoring System (IPSS) score allowed a distinction to be made between a stable disease and hematologic transformation. Chemotherapy is of limited efficacy, and has a high toxicity with severe infectious complications. As the mortality rate is high in our cohort (up to 35% at the age of 40), hematopoietic stem cell transplantation (HSCT) remains the best choice of treatment to avoid severe infectious and/or hematologic complications. The timing of HSCT remains difficult to determine, but the earlier it is performed, the better the outcome.


Assuntos
Deficiência de GATA2/epidemiologia , Mutação em Linhagem Germinativa , Adulto Jovem , Adolescente , Adulto , Bélgica , Criança , Pré-Escolar , França , Deficiência de GATA2/complicações , Deficiência de GATA2/genética , Deficiência de GATA2/terapia , Neoplasias Hematológicas/etiologia , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Lactente , Recém-Nascido , Infecções/etiologia , Pessoa de Meia-Idade , Mortalidade , Prognóstico , Inquéritos e Questionários
6.
Oncotarget ; 7(27): 41599-41611, 2016 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-27191650

RESUMO

T cell acute lymphoblastic leukemia (T-ALL) develops through accumulation of multiple genomic alterations within T-cell progenitors resulting in clonal heterogeneity among leukemic cells. Human T-ALL xeno-transplantation in immunodeficient mice is a gold standard approach to study leukemia biology and we recently uncovered that the leukemia development is more or less rapid depending on T-ALL sample. The resulting human leukemia may arise through genetic selection and we previously showed that human T-ALL development in immune-deficient mice is significantly enhanced upon CD7+/CD34+ leukemic cell transplantations. Here we investigated the genetic characteristics of CD7+/CD34+ and CD7+/CD34- cells from newly diagnosed human T-ALL and correlated it to the speed of leukemia development. We observed that CD7+/CD34+ or CD7+/CD34- T-ALL cells that promote leukemia within a short-time period are genetically similar, as well as xenograft-derived leukemia resulting from both cell fractions. In the case of delayed T-ALL growth CD7+/CD34+ or CD7+/CD34- cells were either genetically diverse, the resulting xenograft leukemia arising from different but branched subclones present in the original sample, or similar, indicating decreased fitness to mouse micro-environment. Altogether, our work provides new information relating the speed of leukemia development in xenografts to the genetic diversity of T-ALL cell compartments.


Assuntos
Variação Genética , Transplante de Neoplasias , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Transplante Heterólogo , Animais , Antígenos CD34/metabolismo , Linhagem Celular Tumoral , Criança , Progressão da Doença , Heterogeneidade Genética , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos Nus , Camundongos SCID , Camundongos Transgênicos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Fatores de Tempo , Adulto Jovem
7.
Eur J Med Genet ; 59(3): 173-8, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26855057

RESUMO

Noonan syndrome is associated with a range of malignancies including acute lymphoblastic leukemia (ALL). However, little information is available regarding the frequency, natural history, characteristics and prognosis of ALL in Noonan syndrome or RASopathies in general. Cross-referencing data from a large prospective cohort of 1176 patients having a molecularly confirmed RASopathy with data from the French childhood cancer registry allowed us to identify ALL in 6 (0.5%) patients including 4/778 (0.5%) with a germline PTPN11 mutation and 2/94 (2.1%) with a germline SOS1 mutation. None of the patients of our series with CFC syndrome (with germline BRAF or MAP2K1/MAP2K2 mutation - n = 121) or Costello syndrome (with HRAS mutation - n = 35) had an ALL. A total of 19 Noonan-ALL were gathered by adding our patients to those of the International Berlin-Munster-Frankfurt (I-BFM) study group and previously reported patients. Strikingly, all Noonan-associated ALL were B-cell precursor ALL, and high hyperdiploidy with more than 50 chromosomes was found in the leukemia cells of 13/17 (76%) patients with available genetics data. Our data suggest that children with Noonan syndrome are at higher risk to develop ALL. Like what is observed for somatic PTPN11 mutations, NS is preferentially associated with the development of hyperdiploid ALL that will usually respond well to chemotherapy. However, Noonan syndrome patients seem to have a propensity to develop post therapy myelodysplasia that can eventually be fatal. Hence, one should be particularly cautious when treating these patients.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiologia , Proteínas ras/genética , Adolescente , Criança , Pré-Escolar , Feminino , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Segunda Neoplasia Primária/etiologia , Síndrome de Noonan/complicações , Síndrome de Noonan/genética , Síndrome de Noonan/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Prevalência , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteína SOS1/genética , Proteínas ras/metabolismo
8.
Eur J Hum Genet ; 24(8): 1124-31, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26757980

RESUMO

Noonan syndrome is a heterogeneous autosomal dominant disorder caused by mutations in at least eight genes involved in the RAS/MAPK signaling pathway. Recently, RIT1 (Ras-like without CAAX 1) has been shown to be involved in the pathogenesis of some patients. We report a series of 44 patients from 30 pedigrees (including nine multiplex families) with mutations in RIT1. These patients display a typical Noonan gestalt and facial phenotype. Among the probands, 8.7% showed postnatal growth retardation, 90% had congenital heart defects, 36% had hypertrophic cardiomyopathy (a lower incidence compared with previous report), 50% displayed speech delay and 52% had learning difficulties, but only 22% required special education. None had major skin anomalies. One child died perinatally of juvenile myelomonocytic leukemia. Compared with the canonical Noonan phenotype linked to PTPN11 mutations, patients with RIT1 mutations appear to be less severely growth retarded and more frequently affected by cardiomyopathy. Based on our experience, we estimate that RIT1 could be the cause of 5% of Noonan syndrome patients. Because mutations found constitutionally in Noonan syndrome are also found in several tumors in adulthood, we evaluated the potential contribution of RIT1 to leukemogenesis in Noonan syndrome. We screened 192 pediatric cases of acute lymphoblastic leukemias (96 B-ALL and 96 T-ALL) and 110 cases of juvenile myelomonocytic leukemias (JMML), but detected no variation in these tumoral samples, suggesting that Noonan patients with germline RIT1 mutations are not at high risk to developing JMML or ALL, and that RIT1 has at most a marginal role in these sporadic malignancies.


Assuntos
Leucemia Mielomonocítica Juvenil/genética , Mutação , Síndrome de Noonan/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas ras/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Leucemia Mielomonocítica Juvenil/patologia , Masculino , Síndrome de Noonan/patologia , Linhagem , Fenótipo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia
9.
Blood ; 127(9): 1163-72, 2016 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-26712910

RESUMO

Juvenile myelomonocytic leukemia (JMML) is a rare and aggressive stem cell disease of early childhood. RAS activation constitutes the core component of oncogenic signaling. In addition, leukemic blasts in one-fourth of JMML patients present with monosomy 7, and more than half of patients show elevated age-adjusted fetal hemoglobin (HbF) levels. Hematopoietic stem cell transplantation is the current standard of care and results in an event-free survival rate of 50% to 60%, indicating that novel molecular-driven therapeutic options are urgently needed. Using gene expression profiling in a series of 82 patient samples, we aimed at understanding the molecular biology behind JMML and identified a previously unrecognized molecular subgroup characterized by high LIN28B expression. LIN28B overexpression was significantly correlated with higher HbF levels, whereas patients with monosomy 7 seldom showed enhanced LIN28B expression. This finding gives a biological explanation of why patients with monosomy 7 are rarely diagnosed with high age-adjusted HbF levels. In addition, this new fetal-like JMML subgroup presented with reduced levels of most members of the let-7 microRNA family and showed characteristic overexpression of genes involved in fetal hematopoiesis and stem cell self-renewal. Lastly, high LIN28B expression was associated with poor clinical outcome in our JMML patient series but was not independent from other prognostic factors such as age and age-adjusted HbF levels. In conclusion, we identified elevated LIN28B expression as a hallmark of a novel fetal-like subgroup in JMML.


Assuntos
Feto/metabolismo , Leucemia Mielomonocítica Juvenil/genética , Proteínas de Ligação a RNA/genética , Biomarcadores Tumorais/metabolismo , Criança , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 7/genética , Intervalo Livre de Doença , Feminino , Hemoglobina Fetal/metabolismo , Regulação Leucêmica da Expressão Gênica , Transplante de Células-Tronco Hematopoéticas , Humanos , Masculino , Análise Multivariada , Prognóstico , Proteínas de Ligação a RNA/metabolismo
10.
Cell Rep ; 13(3): 504-515, 2015 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-26456833

RESUMO

Somatic PTPN11 mutations cause juvenile myelomonocytic leukemia (JMML). Germline PTPN11 defects cause Noonan syndrome (NS), and specific inherited mutations cause NS/JMML. Here, we report that hematopoietic cells differentiated from human induced pluripotent stem cells (hiPSCs) harboring NS/JMML-causing PTPN11 mutations recapitulated JMML features. hiPSC-derived NS/JMML myeloid cells exhibited increased signaling through STAT5 and upregulation of miR-223 and miR-15a. Similarly, miR-223 and miR-15a were upregulated in 11/19 JMML bone marrow mononuclear cells harboring PTPN11 mutations, but not those without PTPN11 defects. Reducing miR-223's function in NS/JMML hiPSCs normalized myelogenesis. MicroRNA target gene expression levels were reduced in hiPSC-derived myeloid cells as well as in JMML cells with PTPN11 mutations. Thus, studying an inherited human cancer syndrome with hiPSCs illuminated early oncogenesis prior to the accumulation of secondary genomic alterations, enabling us to discover microRNA dysregulation, establishing a genotype-phenotype association for JMML and providing therapeutic targets.


Assuntos
Células-Tronco Pluripotentes Induzidas/citologia , Leucemia Mielomonocítica Juvenil/metabolismo , Células Mieloides/citologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Células Cultivadas , Células HEK293 , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Leucemia Mielomonocítica Juvenil/genética , Leucemia Mielomonocítica Juvenil/patologia , MicroRNAs/genética , Mutação , Células Mieloides/metabolismo , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Regulação para Cima
11.
Nat Genet ; 47(11): 1334-40, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26457648

RESUMO

Juvenile myelomonocytic leukemia (JMML) is a rare and severe myelodysplastic and myeloproliferative neoplasm of early childhood initiated by germline or somatic RAS-activating mutations. Genetic profiling and whole-exome sequencing of a large JMML cohort (118 and 30 cases, respectively) uncovered additional genetic abnormalities in 56 cases (47%). Somatic events were rare (0.38 events/Mb/case) and restricted to sporadic (49/78; 63%) or neurofibromatosis type 1 (NF1)-associated (8/8; 100%) JMML cases. Multiple concomitant genetic hits targeting the RAS pathway were identified in 13 of 78 cases (17%), disproving the concept of mutually exclusive RAS pathway mutations and defining new pathways activated in JMML involving phosphoinositide 3-kinase (PI3K) and the mTORC2 complex through RAC2 mutation. Furthermore, this study highlights PRC2 loss (26/78; 33% of sporadic JMML cases) that switches the methylation/acetylation status of lysine 27 of histone H3 in JMML cases with altered RAS and PRC2 pathways. Finally, the association between JMML outcome and mutational profile suggests a dose-dependent effect for RAS pathway activation, distinguishing very aggressive JMML rapidly progressing to acute myeloid leukemia.


Assuntos
Redes Reguladoras de Genes/genética , Leucemia Mielomonocítica Juvenil/genética , Mutação , Complexo Repressor Polycomb 2/genética , Transdução de Sinais/genética , Proteínas ras/genética , Acetilação , Doença Aguda , Criança , Pré-Escolar , Variações do Número de Cópias de DNA , Progressão da Doença , Feminino , Histonas/metabolismo , Humanos , Lactente , Leucemia Mieloide/genética , Leucemia Mieloide/metabolismo , Leucemia Mielomonocítica Juvenil/metabolismo , Masculino , Metilação , Microscopia Confocal , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Complexo Repressor Polycomb 2/metabolismo , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Análise de Sequência de DNA/métodos , Análise de Sobrevida , Transcriptoma , Proteínas ras/metabolismo
12.
Haematologica ; 100(10): 1311-9, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26137961

RESUMO

DNA copy number analysis has been instrumental for the identification of genetic alterations in B-cell precursor acute lymphoblastic leukemia. Notably, some of these genetic defects have been associated with poor treatment outcome and might be relevant for future risk stratification. In this study, we characterized recurrent deletions of CD200 and BTLA genes, mediated by recombination-activating genes, and used breakpoint-specific polymerase chain reaction assay to screen a cohort of 1154 cases of B-cell precursor acute lymphoblastic leukemia uniformly treated according to the EORTC-CLG 58951 protocol. CD200/BTLA deletions were identified in 56 of the patients (4.8%) and were associated with an inferior 8-year event free survival in this treatment protocol [70.2% ± 1.2% for patients with deletions versus 83.5% ± 6.4% for non-deleted cases (hazard ratio 2.02; 95% confidence interval 1.23-3.32; P=0.005)]. Genetically, CD200/BTLA deletions were strongly associated with ETV6-RUNX1-positive leukemias (P<0.0001), but were also identified in patients who did not have any genetic abnormality that is currently used for risk stratification. Within the latter population of patients, the presence of CD200/BTLA deletions was associated with inferior event-free survival and overall survival. Moreover, the multivariate Cox model indicated that these deletions had independent prognostic impact on event-free survival when adjusting for conventional risk criteria. All together, these findings further underscore the rationale for copy number profiling as an important tool for risk stratification in human B-cell precursor acute lymphoblastic leukemia. This trial was registered at www.ClinicalTrials.gov as #NCT00003728.


Assuntos
Antígenos CD/genética , Deleção de Genes , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Receptores Imunológicos/genética , Adolescente , Alelos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Pontos de Quebra do Cromossomo , Ensaios Clínicos como Assunto , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Feminino , Frequência do Gene , Humanos , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Prognóstico , Recidiva
13.
J Med Genet ; 51(10): 689-97, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25097206

RESUMO

BACKGROUND: Infants with Noonan syndrome (NS) are predisposed to developing juvenile myelomonocytic leukaemia (JMML) or JMML-like myeloproliferative disorders (MPD). Whereas sporadic JMML is known to be aggressive, JMML occurring in patients with NS is often considered as benign and transitory. However, little information is available regarding the occurrence and characteristics of JMML in NS. METHODS AND RESULTS: Within a large prospective cohort of 641 patients with a germline PTPN11 mutation, we identified MPD features in 36 (5.6%) patients, including 20 patients (3%) who fully met the consensus diagnostic criteria for JMML. Sixty percent of the latter (12/20) had severe neonatal manifestations, and 10/20 died in the first month of life. Almost all (11/12) patients with severe neonatal JMML were males. Two females who survived MPD/JMML subsequently developed another malignancy during childhood. Although the risk of developing MPD/JMML could not be fully predicted by the underlying PTPN11 mutation, some germline PTPN11 mutations were preferentially associated with myeloproliferation: 10/48 patients with NS (20.8%) with a mutation in codon Asp61 developed MPD/JMML in infancy. Patients with a p.Thr73Ile mutation also had more chances of developing MPD/JMML but with a milder clinical course. SNP array and whole exome sequencing in paired tumoral and constitutional samples identified no second acquired somatic mutation to explain the occurrence of myeloproliferation. CONCLUSIONS: JMML represents the first cause of death in PTPN11-associated NS. Few patients have been reported so far, suggesting that JMML may sometimes be overlooked due to early death, comorbidities or lack of confirmatory tests.


Assuntos
Leucemia Mielomonocítica Juvenil/complicações , Leucemia Mielomonocítica Juvenil/genética , Síndrome de Noonan/complicações , Síndrome de Noonan/genética , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Leucemia Mielomonocítica Juvenil/mortalidade , Leucemia Mielomonocítica Juvenil/fisiopatologia , Masculino , Mutação , Síndrome de Noonan/mortalidade , Síndrome de Noonan/fisiopatologia , Estudos Prospectivos , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética
14.
Hum Mol Genet ; 23(16): 4315-27, 2014 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-24705357

RESUMO

RASopathies, a family of disorders characterized by cardiac defects, defective growth, facial dysmorphism, variable cognitive deficits and predisposition to certain malignancies, are caused by constitutional dysregulation of RAS signalling predominantly through the RAF/MEK/ERK (MAPK) cascade. We report on two germline mutations (p.Gly39dup and p.Val55Met) in RRAS, a gene encoding a small monomeric GTPase controlling cell adhesion, spreading and migration, underlying a rare (2 subjects among 504 individuals analysed) and variable phenotype with features partially overlapping Noonan syndrome, the most common RASopathy. We also identified somatic RRAS mutations (p.Gly39dup and p.Gln87Leu) in 2 of 110 cases of non-syndromic juvenile myelomonocytic leukaemia, a childhood myeloproliferative/myelodysplastic disease caused by upregulated RAS signalling, defining an atypical form of this haematological disorder rapidly progressing to acute myeloid leukaemia. Two of the three identified mutations affected known oncogenic hotspots of RAS genes and conferred variably enhanced RRAS function and stimulus-dependent MAPK activation. Expression of an RRAS mutant homolog in Caenorhabditis elegans enhanced RAS signalling and engendered protruding vulva, a phenotype previously linked to the RASopathy-causing SHOC2(S2G) mutant. Overall, these findings provide evidence of a functional link between RRAS and MAPK signalling and reveal an unpredicted role of enhanced RRAS function in human disease.


Assuntos
Carcinogênese/genética , Mutação/fisiologia , Fenótipo , Proteínas ras/genética , Animais , Caenorhabditis elegans , Estudos de Coortes , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mielomonocítica Juvenil/genética , MAP Quinase Quinase Quinases/metabolismo , Síndrome de Noonan/genética , Proteína Oncogênica v-akt/metabolismo , Transdução de Sinais/genética , Proteínas ras/química , Proteínas ras/metabolismo
15.
Haematologica ; 98(4): 597-601, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23065506

RESUMO

Deletion of the Ikaros (IKZF1) gene is an oncogenic lesion frequently associated with BCR-ABL1-positive acute lymphoblastic leukemias. It is also found in a fraction of BCR-ABL1-negative B-cell precursor acute lymphoblastic leukemias, and early studies showed it was associated with a higher risk of relapse. Therefore, screening tools are needed for evaluation in treatment protocols and possible inclusion in risk stratification. Besides monosomy 7 and large 7p abnormalities encompassing IKZF1, most IKZF1 alterations are short, intragenic deletions. Based on cohorts of patients, we mapped the microdeletion breakpoints and developed a breakpoint-specific fluorescent multiplex polymerase chain reaction that allows detection of recurrent intragenic deletions. This sensitive test could also detect IKZF1 subclonal deletions, whose prognostic significance should be evaluated. Moreover, we show that consensus breakpoint sequences can be used as clonal markers to monitor minimal residual disease. This paper could be useful for translational studies and in clinical management of BCP-ALL.


Assuntos
Fator de Transcrição Ikaros/genética , Reação em Cadeia da Polimerase Multiplex/métodos , Neoplasia Residual/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Deleção de Sequência , Adolescente , Criança , Pré-Escolar , Pontos de Quebra do Cromossomo , Mapeamento Cromossômico , Cromossomos Humanos Par 7/genética , Estudos de Coortes , Hibridização Genômica Comparativa , DNA Intergênico/genética , Feminino , Testes Genéticos/métodos , Humanos , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Prognóstico , Reprodutibilidade dos Testes , Fatores de Risco , Sensibilidade e Especificidade
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