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2.
Ann Hematol ; 97(8): 1349-1356, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29572561

RESUMO

The coexistence of autoimmune disorders (AD) in patients with myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML) has been widely recognized, although with distinct results regarding their prevalence and impact on the outcomes of the underlying hematological process. This study was aimed to analyze the prevalence, clinical characteristics, and outcomes of MDS with AD in a series of 142 patients diagnosed with MDS and CMML. AD was ascertained by both the presence of clinical symptoms or compatible serological tests. In total, 48% patients were diagnosed as having AD, being hypothyroidism the most commonly reported clinical AD (8%) and antinuclear antibodies the most frequent serological parameter identified (23.2%). The presence of AD was associated with female gender, lower hemoglobin levels, and higher IPSS-R. Overall survival for patients with AD was inferior to those with no AD (69 vs. 88% at 30 months; HR 2.75, P = 0.008). Notably, clinical but not isolated immune serological parameters had an impact on the outcomes of patients with AD. Finally, in a multivariate analysis, the presence of AD (HR 2.26) along with disease risk categories (very low and low vs. intermediate, high, and very high IPSS-R; HR 4.62) retained their independent prognostic value (P < 0.001). In conclusion, AD are prevalent in MDS and CMML patients and have prognostic implications, especially in lower-risk MDS patients.


Assuntos
Doenças Autoimunes/complicações , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/epidemiologia , Doenças Autoimunes/imunologia , Biomarcadores , Feminino , Humanos , Incidência , Leucemia Mielomonocítica Crônica/epidemiologia , Leucemia Mielomonocítica Crônica/etiologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Avaliação de Resultados da Assistência ao Paciente , Prevalência , Prognóstico , Adulto Jovem
3.
Leukemia ; 32(6): 1458-1465, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29479066

RESUMO

Recurrent somatic loss-of-function mutations in histone demethylases are frequently detected in cancer. However, whether loss of a histone demethylase can cause cancer has not been determined. Here, we report that knockout of the histone demethylase Utx in mice causes a chronic myelomonocytic leukemia (CMML)-like disease with splenomegaly, monocytosis, and extramedullary hematopoiesis. Mutational analysis of patient data indicated that UTX mutations occur simultaneously with TP53 mutations in myeloid malignancies, and combined inactivation of Utx and Trp53 accelerated the development of CMML in a cell-autonomous manner. Utx loss caused increased self-renewal of hematopoietic stem cells and predisposed hematopoietic stem cells to differentiate into myeloid-derived lineages. Transcriptome and chromatin immunoprecipitation analyses revealed that Utx activates key transcriptional factors required for erythroid differentiation by modulating histone H3 lysine 27 and lysine 4 trimethylation. Our results suggest that Utx suppresses CMML formation by controlling hematopoietic stem cell self-renewal and differentiation.


Assuntos
Histona Desmetilases/genética , Leucemia Mielomonocítica Crônica/etiologia , Mutação , Animais , Diferenciação Celular , Linhagem da Célula , Genes p53 , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/fisiologia , Histona Desmetilases/fisiologia , Histonas/metabolismo , Camundongos , Camundongos Knockout
4.
Epigenetics ; 13(1): 8-18, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29160764

RESUMO

Chromosomal abnormalities are detected in 20-30% of patients with chronic myelomonocytic leukemia (CMML) and correlate with prognosis. On the mutation level, disruptive alterations are particularly frequent in chromatin regulatory genes. However, little is known about the consequential alterations in the epigenetic marking of the genome. Here, we report the analysis of genomic DNA methylation patterns of 64 CMML patients and 10 healthy controls, using a DNA methylation microarray focused on promoter regions. Differential methylation analysis between patients and controls allowed us to identify abnormalities in DNA methylation, including hypermethylation of specific genes and large genome regions with aberrant DNA methylation. Unsupervised hierarchical cluster analysis identified two main clusters that associated with the clinical, biological, and genetic features of patients. Group 1 was enriched in patients with adverse clinical and biological characteristics and poorer overall and progression-free survival. In addition, significant differences in DNA methylation were observed between patients with low risk and intermediate/high risk karyotypes and between TET2 mutant and wild type patients. Taken together, our results demonstrate that altered DNA methylation patterns reflect the CMML disease state and allow to identify patient groups with distinct clinical features.


Assuntos
Metilação de DNA , Leucemia Mielomonocítica Crônica/genética , Leucemia Mielomonocítica Crônica/mortalidade , Idoso , Estudos de Casos e Controles , Proteínas de Ligação a DNA/genética , Intervalo Livre de Doença , Epigênese Genética , Feminino , Regulação Leucêmica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Leucemia Mielomonocítica Crônica/etiologia , Masculino , Mutação , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Proteínas Proto-Oncogênicas/genética
5.
J Cancer Res Ther ; 11(4): 914-6, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26881541

RESUMO

Myeloid neoplasms associated with platelet-derived growth factor b (PDGFRB) rearrangement usually keep only one morphologic type unless blast crisis. We describe a unique case of hematological features transformation from atypical chronic myeloid leukemia to chronic myelomonocytic leukemia, and imatinib showed no clinical therapeutic effects. The phenomenon indicates that different types of myeloid neoplasms associated with PDGFRB rearrangement can transform into one another with the progression of the disease, and to some extent, this transformation suggests the aggravation of disease.


Assuntos
Transformação Celular Neoplásica/genética , Rearranjo Gênico , Leucemia Mieloide Crônica Atípica BCR-ABL Negativa/complicações , Leucemia Mielomonocítica Crônica/patologia , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Adulto , Transformação Celular Neoplásica/patologia , Progressão da Doença , Humanos , Leucemia Mieloide Crônica Atípica BCR-ABL Negativa/genética , Leucemia Mieloide Crônica Atípica BCR-ABL Negativa/patologia , Leucemia Mielomonocítica Crônica/etiologia , Masculino , Prognóstico
6.
Clin Lymphoma Myeloma Leuk ; 15(2): 110-4, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25107338

RESUMO

BACKGROUND: Patients with multiple myeloma (MM) have had significant improvements in outcomes. An increased risk of therapy-related myeloid neoplasms (t-MNs) has also developed. Little is known about the characteristics and outcomes of these patients. PATIENTS AND METHODS: Patients with MM treated at our institution from 1993 to 2011 were reviewed. Forty-seven patients were diagnosed with t-MN. Our primary objective was to evaluate the interval to t-MN, response to treatment, and overall survival (OS). RESULTS: The median patient age at the MM diagnosis was 65 years. Of the 47 patients, 32 (68.0%) initially received conventional chemotherapeutic agents, 7 (14.9%), novel agents (eg, lenalidomide, thalidomide, bortezomib), and 8 (17.0%), a combination. Twenty patients (42.6%) underwent high-dose chemotherapy and autologous hematopoietic stem cell transplantation. The median interval from the MM diagnosis to t-MN was 7 years (95% CI, 5.0-28.0). Of the 47 patients, 33 (70.2%) developed therapy-related myelodysplastic syndrome (t-MDS), 11 (23.4%) acute myeloid leukemia (t-AML), and 3 (6.4%) chronic myelomonocytic leukemia (t-CMML). The median age at the t-MN diagnosis was 65 years. Of the 47 patients, 26 (78.8%) with t-MDS, 9 (81.8%) with t-AML, and 1 (33.3%) with t-CMML had complex/high-risk cytogenetics. The median OS for all 47 patients after the t-MN diagnosis was 6.3 months (95% CI, 4.0-8.7). CONCLUSION: The development of t-MN in patients with MM is associated with poor outcomes. These patients, in general, have complex cytogenetic abnormalities and short complete remission and OS times. A better understanding of the disease biology and novel therapeutic approaches are warranted.


Assuntos
Leucemia Mieloide Aguda/etiologia , Leucemia Mielomonocítica Crônica/etiologia , Mieloma Múltiplo/patologia , Mieloma Múltiplo/terapia , Síndromes Mielodisplásicas/etiologia , Segunda Neoplasia Primária/etiologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Resultado do Tratamento
7.
Arch Environ Occup Health ; 67(4): 206-18, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23074978

RESUMO

The authors report the results of a hospital-based case-control study of all patients diagnosed with chronic myelomonocytic leukemia (CMML) (n = 36) from 28 participating hospitals over a 4-year period. Diagnoses were made by a single laboratory using 2001 World Health Organization (WHO) criteria. Subjects were matched to 2 control patients and interviewed concerning previous diseases, work histories, and exposures to potential etiologic agents. Peripheral blood and bone marrow findings revealed clinical features of both myelodysplastic syndromes (MDSs) and myeloproliferative neoplasms (MPNs), consistent with hematopoietic disease category of MDS/MPN. The frequency of clonal cytogenetic abnormalities in all CMML cases was 31%, with no consistent pattern identified. A select number of risk factors associated with occupational exposure, nonoccupational exposure, and prior medical or family history of disease were extracted from the questionnaire. The results were compared between the case and control subjects. A total of 5 study subjects (2 CMML cases and 3 control subjects) were determined to have had some benzene exposure. In addition, none of the highlighted risk factors associated with nonoccupational exposure to etiologic agents was significantly different among the study subjects. These results do not support an increased risk for developing CMML associated with historical exposures to benzene.


Assuntos
Benzeno/efeitos adversos , Carcinógenos Ambientais/efeitos adversos , Leucemia Mielomonocítica Crônica/etiologia , Exposição Ocupacional/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , China , Exposição Ambiental/efeitos adversos , Exposição Ambiental/estatística & dados numéricos , Feminino , Humanos , Hibridização in Situ Fluorescente , Leucemia Mielomonocítica Crônica/diagnóstico , Leucemia Mielomonocítica Crônica/genética , Masculino , Pessoa de Meia-Idade , Exposição Ocupacional/estatística & dados numéricos , Razão de Chances , Estudos Prospectivos , Fatores de Risco , Inquéritos e Questionários
8.
Blood ; 119(11): 2612-4, 2012 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-22138511

RESUMO

Familial platelet disorder with a propensity to develop acute myeloid leukemia (FPD/AML) is a rare autosomal dominant disease characterized by thrombocytopenia, abnormal platelet function, and a propensity to develop myelodysplastic syndrome (MDS) and AML. So far, > 20 affected families have been reported. Recently, a second RUNX1 alteration has been reported; however, no additional molecular abnormalities have been found so far. We identified an acquired CBL mutation and 11q-acquired uniparental disomy (11q-aUPD) in a patient with chronic myelomonocytic leukemia (CMML) secondary to FPD with RUNX1 mutation but not in the same patient during refractory cytopenia. This finding suggests that alterations of the CBL gene and RUNX1 gene may cooperate in the pathogenesis of CMML in patients with FPD/AML. The presence of CBL mutations and 11q-aUPD was an important "second hit" that could be an indicator of leukemic transformation of MDS or AML in patients with FPD/AML.


Assuntos
Transtornos Plaquetários/genética , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Predisposição Genética para Doença , Leucemia Mieloide Aguda/genética , Leucemia Mielomonocítica Crônica/etiologia , Mutação/genética , Proteínas Proto-Oncogênicas c-cbl/genética , Adulto , Transtornos Plaquetários/complicações , Criança , Cromossomos Humanos Par 11/genética , Feminino , Genes Dominantes , Haplótipos/genética , Humanos , Immunoblotting , Leucemia Mieloide Aguda/complicações , Masculino , Pessoa de Meia-Idade , Linhagem , Reação em Cadeia da Polimerase
9.
Blood ; 116(26): 6003-13, 2010 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-20858858

RESUMO

Hyperactivation of the transcription factor Stat5 leads to various leukemias. Stat5 activity is regulated by the protein phosphatase SHP-1 in a phospholipase C (PLC)-ß3-dependent manner. Thus, PLC-ß3-deficient mice develop myeloproliferative neoplasm, like Lyn (Src family kinase)- deficient mice. Here we show that Lyn/PLC-ß3 doubly deficient lyn(-/-);PLC-ß3(-/-) mice develop a Stat5-dependent, fatal myelodysplastic/myeloproliferative neoplasm, similar to human chronic myelomonocytic leukemia (CMML). In hematopoietic stem cells of lyn(-/-);PLC-ß3(-/-) mice that cause the CMML-like disease, phosphorylation of SHP-1 at Tyr(536) and Tyr(564) is abrogated, resulting in reduced phosphatase activity and constitutive activation of Stat5. Furthermore, SHP-1 phosphorylation at Tyr(564) by Lyn is indispensable for maximal phosphatase activity and for suppression of the CMML-like disease in these mice. On the other hand, Tyr(536) in SHP-1 can be phosphorylated by Lyn and another kinase(s) and is necessary for efficient interaction with Stat5. Therefore, we identify a novel Lyn/PLC-ß3-mediated regulatory mechanism of SHP-1 and Stat5 activities.


Assuntos
Leucemia Mielomonocítica Crônica/metabolismo , Transtornos Mieloproliferativos/metabolismo , Fosfolipase C beta/fisiologia , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Fator de Transcrição STAT5/metabolismo , Quinases da Família src/fisiologia , Animais , Feminino , Células-Tronco Hematopoéticas/metabolismo , Humanos , Immunoblotting , Imunoprecipitação , Inflamação/etiologia , Inflamação/patologia , Janus Quinase 2/metabolismo , Leucemia Mielomonocítica Crônica/etiologia , Leucemia Mielomonocítica Crônica/patologia , Pneumopatias/etiologia , Pneumopatias/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transtornos Mieloproliferativos/etiologia , Transtornos Mieloproliferativos/patologia , Fenótipo , Fosforilação , Transdução de Sinais , Tirosina/metabolismo , Quinases da Família src/metabolismo
11.
Leuk Lymphoma ; 49(7): 1292-6, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18604717

RESUMO

From a retrospective analysis of our series of myelodysplastic patients, we found 16 patients who were initially diagnosed as having a refractory anemia with excess of blasts (RAEB) according to FAB criteria, but later on (median time 4 months, range 2-8) developed a peripheral monocytosis >1 x 10(9)/L, leading to a disease re-classification into a dysplastic type of chronic myelomonocytic leukemia (MD-CMML). Analysis of clinical and prognostic aspects in this subgroup of patients as compared with those of primarily diagnosed MD-CMML patients, showed some significant differences in Hb level, platelet count, percentage of immature circulating precursor (IPC), bone marrow blastosis and trilineage dysplasia. Median survival for present group of patients was 33 months compared with 20 months for MD-CMML. Different prognostic scores were applied for evaluation of risk distribution and relative impact on survival prediction. We suggest on a possible atypical presentation of CMML and indicate a careful attention to be addressed to myelodysplastic patients who develop peripheral monocytosis, who might have a CMML variant, with more favourable prognosis and prolonged survival. Furthermore, we believe this is a further evidence for the arbitrary nature of current classification systems, which definitely exclude CMML from myelodysplastic syndromes.


Assuntos
Anemia Refratária com Excesso de Blastos/patologia , Leucemia Mielomonocítica Crônica/classificação , Síndromes Mielodisplásicas/classificação , Idoso , Células da Medula Óssea/patologia , Progressão da Doença , Feminino , Humanos , Leucemia Mielomonocítica Crônica/diagnóstico , Leucemia Mielomonocítica Crônica/etiologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Organização Mundial da Saúde
12.
Leukemia ; 22(7): 1335-42, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18548091

RESUMO

In 1982, chronic myelomonocytic leukemia (CMML) was first classified in the category of myelodysplastic syndromes (MDSs), but it always seemed somewhat out of place compared with the rest of the MDS categories. In the 1990s, many argued that there were two different forms of CMML, a proliferative type and a myelodysplastic type. Then in 2001 the World Health Organization created a new category called the mixed myelodysplastic/myeloproliferative diseases, under which CMML was included. Although we still do not understand much about CMML pathogenesis nor do we have specific therapies for this disease, at least now most agree that it is in an appropriate category such that other areas of investigation can now proceed. On the other hand, we now understand a great deal of the pathogenesis underlying the disease now called juvenile myelomonocytic leukemia (JMML). JMML also fits in the new category of mixed myelodysplastic/myeloproliferative diseases. JMML is an excellent model malignancy for investigating and understanding dysregulated and aberrant signal transduction in the Ras pathway. It has also served as a teaching tool for exploring inherited predispositions to cancer.


Assuntos
Leucemia Mielomonocítica Crônica/classificação , Leucemia Mielomonocítica Juvenil/classificação , Humanos , Leucemia Mielomonocítica Crônica/diagnóstico , Leucemia Mielomonocítica Crônica/tratamento farmacológico , Leucemia Mielomonocítica Crônica/etiologia , Leucemia Mielomonocítica Juvenil/diagnóstico
13.
Leuk Lymphoma ; 48(6): 1150-60, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17577778

RESUMO

Chronic myelomonocytic leukemia continues to be a poorly understood disease, defined by clinical rather than biological features, with no consensus on optimal therapy. In the past, patients were often assessed for risk using scoring systems developed for other diseases, notably the International Prognostic Scoring System commonly used for myelodysplastic syndrome. The M.D. Anderson Prognostic Scoring System, using hemoglobin, absolute lymphocyte count, peripheral blood immature cells, and bone marrow blasts, was developed specifically for CMML; it was based on retrospective analysis of 213 patients. This report re-examines the validity of this scoring system based on follow-up of the initial cohort and prospectively examines its validity in 250 new patients. Both the original MDAPS system and a modified version derived from data of the initial cohort after extended follow-up (substituting lactate dehydrogenase for bone marrow blasts) effectively stratify both patient cohorts by survival and provide a useful risk assessment tool and additional guidance during treatment decisions.


Assuntos
Leucemia Mielomonocítica Crônica/diagnóstico , Leucemia Mielomonocítica Crônica/etiologia , Leucemia Mielomonocítica Crônica/patologia , Estadiamento de Neoplasias/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Seguimentos , Humanos , Leucemia Mielomonocítica Crônica/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Projetos de Pesquisa , Medição de Risco , Fatores de Risco , Análise de Sobrevida
14.
Blood ; 109(4): 1687-91, 2007 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-17090653

RESUMO

Neurofibromatosis type 1 (NF1) syndrome is caused by germline mutations in the NF1 tumor suppressor, which encodes neurofibromin, a GTPase activating protein for Ras. Children with NF1 are predisposed to juvenile myelomonocytic leukemia (JMML) and lethally irradiated mice given transplants with homozygous Nf1 mutant (Nf1-/-) hematopoietic stem cells develop a fatal myeloproliferative disorder (MPD) that models JMML. We investigated the requirement for signaling through the GM-CSF receptor to initiate and sustain this MPD by generating Nf1 mutant hematopoietic cells lacking the common beta chain (Beta c) of the GM-CSF receptor. Mice reconstituted with Nf1-/-, beta c-/- stem cells did not develop evidence of MPD despite the presence of increased number of immature hematopoietic progenitors in the bone marrow. Interestingly, when the Mx1-Cre transgene was used to inactivate a conditional Nf1 mutant allele in hematopoietic cells, concomitant loss of beta c-/- reduced the severity of the MPD, but did not abrogate it. Whereas inhibiting GM-CSF signaling may be of therapeutic benefit in JMML, our data also demonstrate aberrant proliferation of Nf1-/-myeloid progenitors that is independent of signaling through the GM-CSF receptor.


Assuntos
Leucemia Mielomonocítica Crônica/etiologia , Transtornos Mieloproliferativos/etiologia , Neurofibromatose 1/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Animais , Modelos Animais de Doenças , Transplante de Células-Tronco Hematopoéticas , Leucemia Mielomonocítica Crônica/prevenção & controle , Camundongos , Camundongos Mutantes , Transtornos Mieloproliferativos/prevenção & controle , Transdução de Sinais
15.
Am J Clin Pathol ; 126(5): 789-97, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17050076

RESUMO

The majority of chronic myelomonocytic leukemia (CMML) cases arise de novo; cases evolving from preexisting myelodysplasia (MDS) or myeloproliferative diseases have not been well-studied. We conducted the present study to determine the clinicopathologic features and to study possible underlying molecular and cytogenetic mechanisms involved in this evolution. Between April 1995 and November 2005, we identified 120 CMML cases, of which 20 (16.7%) had a previous diagnosis of MDS. Of the 20 patients with MDS, 6 had relative monocytosis at diagnosis. At the time of MDS to CMML evolution, mutations in JAK2 (V617F), FLT3 (ITD), K-ras-2, or N-ras were not acquired, and only 1 (6%) of 17 evaluable cases showed cytogenetic progression. The median time to evolution from MDS to CMML was 29 months, and the median survival following CMML development was 13 months. Three cases (17%) transformed to acute myeloid leukemia. These findings indicate that in some cases of otherwise typical MDS, the progenitor cells may have some capacity for monocytic proliferation at diagnosis and manifest rapid disease progression once a monocytic proliferation supervenes.


Assuntos
Leucemia Mielomonocítica Crônica/patologia , Transtornos Mieloproliferativos/complicações , Defeitos do Tubo Neural/complicações , Idoso , Idoso de 80 Anos ou mais , DNA/química , DNA/genética , Análise Mutacional de DNA , Humanos , Janus Quinase 2/genética , Estimativa de Kaplan-Meier , Cariotipagem , Leucemia Mielomonocítica Crônica/etiologia , Leucemia Mielomonocítica Crônica/genética , Masculino , Pessoa de Meia-Idade , Mutação/genética , Tirosina Quinase 3 Semelhante a fms/genética , Proteínas ras/genética
17.
Blood ; 105(9): 3737-42, 2005 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-15644411

RESUMO

Juvenile myelomonocytic leukemia (JMML) is a lethal disease of young children characterized by hypersensitivity of hematopoietic progenitors to granulocyte-macrophage colony-stimulating factor (GM-CSF). Mutations in PTPN11, which encodes the protein tyrosine phosphatase Shp-2, are common in JMML. We hypothesized that PTPN11 mutations induce hypersensitivity of hematopoietic progenitors to GM-CSF and confer increased GM-CSF-stimulated phospho-extracellular signal-regulated kinase (Erk) levels. To test this hypothesis, the wild-type (WT) and 3 mutant Ptpn11 cDNAs (E76K, D61V, and D61Y) were transduced into murine bone marrow cells to examine GM-CSF-stimulated granulocyte-macrophage colony-forming unit (CFU-GM) growth, macrophage progenitor proliferation, and activation of the Ras signaling pathway. Expression of the Shp-2 mutants induced progenitor cell hypersensitivity to GM-CSF compared with cells transduced with vector alone or WT Shp-2. Macrophage progenitors expressing the Shp-2 mutants displayed both basal and GM-CSF-stimulated hyperproliferation compared with cells transduced with vector alone or WT Shp-2. Consistently, macrophage progenitors transduced with the Shp-2 mutants demonstrated constitutively elevated phospho-Erk levels and sustained activation of phospho-Erk following GM-CSF stimulation compared with vector alone or WT Shp-2. These data support the hypothesis that PTPN11 mutations induce hematopoietic progenitor hypersensitivity to GM-CSF due to hyperactivation of the Ras signaling axis and provide a basis for the GM-CSF signaling pathway as a target for rational drug design in JMML.


Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Mutação Puntual , Proteínas Tirosina Fosfatases/genética , Animais , Células da Medula Óssea/metabolismo , Proliferação de Células , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Leucemia Mielomonocítica Crônica/etiologia , Leucemia Mielomonocítica Crônica/metabolismo , Leucemia Mielomonocítica Crônica/patologia , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Proteína Tirosina Fosfatase não Receptora Tipo 11 , Transdução de Sinais , Transdução Genética , Proteínas ras/metabolismo
18.
Curr Hematol Rep ; 3(3): 203-9, 2004 May.
Artigo em Inglês | MEDLINE | ID: mdl-15087069

RESUMO

Juvenile myelomonocytic leukemia (JMML) is a rare, clonal, mixed myeloproliferative and myelodysplastic disorder afflicting young children. Patients with JMML respond poorly to most standard chemotherapy regimens and, whereas stem cell transplantation is the only known curative approach, even this modality is hampered by high relapse rates. The pathogenesis of JMML arises from dysregulation of signal transduction through the Ras pathway. This dysregulation results in JMML cells demonstrating selective hypersensitivity in vitro to granulocyte macrophage colony-stimulating factor (GM-CSF). Potential causative mutations or other genetic abnormalities in three genes (eg, RAS, neurofibromatosis type 1, and PTPN11), all of which are positioned in the GM-CSF/Ras signal transduction pathway, account for up to 75% of cases of JMML. These pathogenetic advances are paving the way for the development and testing of mechanism-based molecularly targeted therapeutics in JMML aimed specifically at the GM-CSF signal transduction pathway through Ras.


Assuntos
Leucemia Mielomonocítica Crônica/etiologia , Algoritmos , Criança , Hematopoese/genética , Humanos , Leucemia Mielomonocítica Crônica/genética , Leucemia Mielomonocítica Crônica/patologia , Leucemia Mielomonocítica Crônica/terapia , Mutação , Neurofibromatose 1/genética , Síndrome de Noonan/genética , Células-Tronco Pluripotentes/patologia
19.
Curr Hematol Rep ; 2(3): 202-8, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12901341

RESUMO

Chronic myelomonocytic leukemia (CMML) is a myeloproliferative disorder with unique characteristics. Dysplasia is usually present in the bone marrow, thus CMML has usually been classified as a myelodysplastic syndrome. The recent World Health Organization classification of myeloid malignancies proposes to classify CMML into a new category of myelodysplastic syndromes and myeloproliferative disorders. A new prognostic score has also been developed exclusively for patients with CMML that recognizes four groups with distinct prognoses. Significant biologic findings in the recent months include the recognition of the importance of angiogenesis in CMML with a possible autocrine role for vascular endothelial growth factor, and the further understanding of the role of tyrosine kinase fusion genes and activation in some patients with CMML Therapeutic discoveries have been hampered by the paucity of studies looking specifically at CMML Among agents with potential significant activity are imatinib mesylate (for patients with platelet-derived growth factor beta receptor-associated fusion genes), hypomethylating agents, antiangiogenic agents, farnesyltransferase inhibitors, and topoisomerase I inhibitors. Future studies should consider CMML as a separate entity to promote a better understanding and identify more effective therapy for patients with this disease.


Assuntos
Leucemia Mielomonocítica Crônica/classificação , Humanos , Leucemia Mielomonocítica Crônica/diagnóstico , Leucemia Mielomonocítica Crônica/etiologia , Leucemia Mielomonocítica Crônica/terapia , Transtornos Mieloproliferativos/classificação , Neovascularização Fisiológica , Prognóstico , Translocação Genética
20.
Haematologica ; 88(4): 408-15, 2003 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12681968

RESUMO

BACKGROUND AND OBJECTIVES: Chronic myelomonocytic leukemia (CMML) is a myelodysplastic syndrome that has been associated with the expression of platelet-derived growth factor b receptor (PDGFRbeta) fusion proteins, namely TEL/PDGFRbeta. These fusion proteins possess a constitutive PDGFRbeta tyrosine kinase activity, leading to aberrant PDGFRbeta signaling and cellular transformation. The expression of PDGFRbeta fusions in CMML could have therapeutic relevance, as PDGFRb is inhibited by the selective tyrosine kinase inhibitor, imatinib. Here, we investigated the possibility of employing imatinib to treat CMML. DESIGN AND METHODS: We assessed the effect of imatinib on TEL/PDGFRbeta transformed cells in terms of proliferation, by trypan blue exclusion and 3H-thymidine uptake, and TEL/PDGFRbeta autophosphorylation by anti-phosphotyrosine immunoblotting. TEL/PDGFRbeta expression in mononuclear cells from the peripheral blood of 27 clinically diagnosed CMML patients was determined by reverse transcriptase-polymerase chain reaction. RESULTS: Imatinib potently inhibited the proliferation of TEL/PDGFRbeta transformed cells (IC50=7.5 nM), and TEL/PDGFRbeta kinase activity. However, TEL/PDGFRbeta expression was detected in only 1 of 27 CMML patients (4%, confidence intervals: 0-13%). Additionally, another PDGFRbeta fusion protein, Hip1/PDGFRbeta, had a similarly low incidence in the same samples: 1 of 25 (4%, confidence intervals: 0-14%). INTERPRETATION AND CONCLUSIONS: Although imatinib represents an attractive therapeutic agent for neoplasias associated with abnormal PDGFRbeta signaling, the low frequency of the TEL/PDGFRbeta and Hip1/PDGFRbeta fusion proteins in CMML suggests that its application to this disease maybe limited. Detection of PDGFRbeta fusion genes in individual patients is necessary in order to employ this drug rationally in CMML.


Assuntos
Leucemia Mielomonocítica Crônica/tratamento farmacológico , Proteínas de Fusão Oncogênica/sangue , Piperazinas/farmacologia , Pirimidinas/farmacologia , Animais , Benzamidas , Linhagem Celular Transformada , Transformação Celular Neoplásica/efeitos dos fármacos , Humanos , Mesilato de Imatinib , Leucemia Mielomonocítica Crônica/etiologia , Leucemia Mielomonocítica Crônica/patologia , Camundongos , Proteínas de Fusão Oncogênica/antagonistas & inibidores , Proteínas de Fusão Oncogênica/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa
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