RESUMO
Mouse models of chronic myeloid malignancies suggest that targeting mature cells of the malignant clone disrupts feedback loops that promote disease expansion. Here, we show that in chronic myelomonocytic leukemia (CMML), monocytes that accumulate in the peripheral blood show a decreased propensity to die by apoptosis. BH3 profiling demonstrates their addiction to myeloid cell leukemia-1 (MCL1), which can be targeted with the small molecule inhibitor S63845. RNA sequencing and DNA methylation pattern analysis both point to the implication of the mitogen-activated protein kinase (MAPK) pathway in the resistance of CMML monocytes to death and reveal an autocrine pathway in which the secreted cytokine-like protein 1 (CYTL1) promotes extracellular signal-regulated kinase (ERK) activation through C-C chemokine receptor type 2 (CCR2). Combined MAPK and MCL1 inhibition restores apoptosis of monocytes from patients with CMML and reduces the expansion of patient-derived xenografts in mice. These results show that the combined inhibition of MCL1 and MAPK is a promising approach to slow down CMML progression by inducing leukemic monocyte apoptosis.
Assuntos
Proteínas Sanguíneas/metabolismo , Citocinas/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Leucemia Mielomonocítica Crônica , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Monócitos , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Sobrevivência Celular/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Humanos , Leucemia Mielomonocítica Crônica/tratamento farmacológico , Leucemia Mielomonocítica Crônica/metabolismo , Leucemia Mielomonocítica Crônica/patologia , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Monócitos/patologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Chronic myelomonocytic leukemia (CMML) is a myelodysplastic syndrome/ myeloproliferative neoplasm whose diagnosis is currently based on the elevation of peripheral blood monocytes to >1 × 10(9)/L, measured for ≥3 months. Diagnosis can be ambiguous; for example, with prefibrotic myelofibrosis or reactive monocytosis. We set up a multiparameter flow cytometry assay to distinguish CD14(+)/CD16(-) classical from CD14(+)/CD16(+) intermediate and CD14(low)/CD16(+) nonclassical monocyte subsets in peripheral blood mononucleated cells and in total blood samples. Compared with healthy donors and patients with reactive monocytosis or another hematologic malignancy, CMML patients demonstrate a characteristic increase in the fraction of CD14(+)/CD16(-) cells (cutoff value, 94.0%). The associated specificity and sensitivity values were 95.1% and 90.6% in the learning cohort (175 samples) and 94.1% and 91.9% in the validation cohort (307 samples), respectively. The accumulation of classical monocytes, which demonstrate a distinct gene expression pattern, is independent of the mutational background. Importantly, this increase disappears in patients who respond to hypomethylating agents. We conclude that an increase in the fraction of classical monocytes to >94.0% of total monocytes is a highly sensitive and specific diagnostic marker that rapidly and accurately distinguishes CMML from confounding diagnoses.
Assuntos
Citometria de Fluxo/métodos , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Receptores de Lipopolissacarídeos/sangue , Monócitos , Receptores de IgG/sangue , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Monócitos/patologia , Sensibilidade e EspecificidadeAssuntos
Leucemia Mielomonocítica Crônica/patologia , Contagem de Leucócitos , Monócitos/patologia , Síndromes Mielodisplásicas/classificação , Corticosteroides/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anti-Inflamatórios/farmacologia , Medula Óssea/patologia , Progressão da Doença , Feminino , Citometria de Fluxo , Seguimentos , Humanos , Inflamação/sangue , Inflamação/tratamento farmacológico , Leucemia Mielomonocítica Crônica/sangue , Masculino , Pessoa de Meia-Idade , Monócitos/classificação , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/patologia , Risco , Adulto JovemRESUMO
The monocyte subset partitioning by flow cytometry, known as "monocyte assay," is now integrated into the new classifications as a supporting criterion for CMML diagnosis, if a relative accumulation of classical monocytes above 94% of total circulating monocytes is observed. Here we provide clinical flow cytometry laboratories with technical support adapted for the most commonly used cytometers. Step-by-step explanations of the gating strategy developed on whole peripheral blood are presented while underlining the most common difficulties. In a second part, interpretation recommendations of circulating monocyte partitioning from the dedicated French working group "CytHem-LMMC" are shared as well as the main pitfalls, including false positive and false negative cases. The particular flow-defined inflammatory profile is described and the usefulness of the nonclassical monocyte specific marker, namely slan, highlighted. Examples of reporting to the physician with frequent situations encountered when using the monocyte assay are also presented.
Assuntos
Citometria de Fluxo , Monócitos , Citometria de Fluxo/métodos , Citometria de Fluxo/normas , Humanos , Monócitos/citologia , Monócitos/imunologia , Imunofenotipagem/métodos , Imunofenotipagem/normasRESUMO
Targeting the reprogramming and phagocytic capacities of tumor-associated macrophages (TAMs) has emerged as a therapeutic opportunity for cancer treatment. Here, we demonstrate that tumor cell phagocytosis drives the pro-inflammatory activation of TAMs and identify a key role for the cyclin-dependent kinase inhibitor CDKN1A (p21). Through the transcriptional repression of Signal-Regularity Protein α (SIRPα), p21 promotes leukemia cell phagocytosis and, subsequently, the pro-inflammatory reprogramming of phagocytic macrophages that extends to surrounding macrophages through Interferon γ. In mouse models of human T-cell acute lymphoblastic leukemia (T-ALL), infusion of human monocytes (Mos) engineered to overexpress p21 (p21TD-Mos) leads to Mo differentiation into phagocytosis-proficient TAMs that, after leukemia cell engulfment, undergo pro-inflammatory activation and trigger the reprogramming of bystander TAMs, reducing the leukemic burden and substantially prolonging survival in mice. These results reveal p21 as a trigger of phagocytosis-guided pro-inflammatory TAM reprogramming and highlight the potential for p21TD-Mo-based cellular therapy as a cancer immunotherapy.
Assuntos
Leucemia Mieloide Aguda , Fagocitose , Humanos , Camundongos , Animais , Imunoterapia , Macrófagos/metabolismo , Leucemia Mieloide Aguda/patologia , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismoRESUMO
Somatic mutation in TET2 gene is one of the most common clonal genetic events detected in age-related clonal hematopoiesis as well as in chronic myelomonocytic leukemia (CMML). In addition to being a pre-malignant state, TET2 mutated clones are associated with an increased risk of death from cardiovascular disease, which could involve cytokine/chemokine overproduction by monocytic cells. Here, we show in mice and in human cells that, in the absence of any inflammatory challenge, TET2 downregulation promotes the production of MIF (macrophage migration inhibitory factor), a pivotal mediator of atherosclerotic lesion formation. In healthy monocytes, TET2 is recruited to MIF promoter and interacts with the transcription factor EGR1 and histone deacetylases. Disruption of these interactions as a consequence of TET2-decreased expression favors EGR1-driven transcription of MIF gene and its secretion. MIF favors monocytic differentiation of myeloid progenitors. These results designate MIF as a chronically overproduced chemokine and a potential therapeutic target in patients with clonal TET2 downregulation in myeloid cells.
Assuntos
Proteínas de Ligação a DNA/metabolismo , Dioxigenases/metabolismo , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Fatores Inibidores da Migração de Macrófagos/metabolismo , Monócitos/metabolismo , Animais , Linhagem Celular , Citocinas/genética , Citocinas/metabolismo , Proteínas de Ligação a DNA/genética , Dioxigenases/genética , Proteína 1 de Resposta de Crescimento Precoce/genética , Regulação da Expressão Gênica/fisiologia , Humanos , Recém-Nascido , Fatores Inibidores da Migração de Macrófagos/genética , CamundongosRESUMO
In the last version of the WHO classification of myeloid malignancies, flow cytometry and molecular investigation are listed as potentially useful, yet non-essential diagnostic tools in hard-to-recognize chronic myelomonocytic leukemias (CMML). Flow recognition of CMML was initially based on an increase in the fraction of peripheral blood, CD14+,CD16- classical monocytes ≥94% of total monocytes. An associated inflammatory disease can preclude the detection of classical monocyte fraction increase by inducing accumulation of CD14+,CD16+ intermediate monocytes. In such a situation, decrease in the Slan+,CD14low,CD16+ non-classical monocyte fraction below 1.7% still supports CMML diagnosis. This robust, two-step flow cytometry assay identifies CMML with a very high sensitivity. Otherwise, detection of one or several acquired gene mutations with high variant allele frequency supports the diagnosis of CMML, oligomonocytic CMML or clonal monocytosis of clinical significance. Together, recent investigations support integration of flow cytometry analysis of peripheral blood monocyte subsets and new generation sequencing of a panel of 20-30 recurrently mutated genes in the diagnostic work-up of CMML.
Assuntos
Citometria de Fluxo , Sequenciamento de Nucleotídeos em Larga Escala , Imunofenotipagem , Humanos , Leucemia Mielomonocítica Crônica/diagnóstico , Leucemia Mielomonocítica Crônica/genéticaRESUMO
BACKGROUND: Accumulation of classical monocytes CD14++ CD16- (also called MO1) ≥ 94% can accurately distinguish chronic myelomonocytic leukemia (CMML) from reactive monocytosis. The HematoFlow™ solution, able to quantify CD16 negative monocytes, could be a useful tool to manage monocytosis which remains a common issue in routine laboratories. METHODS: Classical monocytes were quantified from 153 whole blood samples collected on EDTA using both flow cytometry methods, either MO1 percentage determination by the multiparameter assay previously published and regarded here as the reference method, or CD16 negative monocyte percentage determination by the means of HematoFlow™. RESULTS: Both methods of classical monocyte percentage determination were highly and significantly correlated (r = 0.87, P < 0.0001). The HematoFlow™ solution leant toward an overestimation of the genuine classical monocyte percentages obtained by the reference method. Percentages of CD16 negative monocytes provided by HematoFlow were higher than 94% for all the 73 patients displaying classical monocytes MO1 found ≥94% by the reference method, indicating a sensitivity of 100%. Furthermore, the calculation of CD16 negative monocyte percentage can be easily computerized and integrated to the middleware. CONCLUSIONS: We propose a new application of the Hematoflow™ solution that can be used as a flag system for monocytosis management and CMML detection. © 2017 International Clinical Cytometry Society.
Assuntos
Citometria de Fluxo , Leucemia Mielomonocítica Crônica/diagnóstico , Humanos , Leucemia Mielomonocítica Crônica/sangue , Sensibilidade e Especificidade , SoluçõesRESUMO
Peripheral blood monocytes include three subsets defined by CD14 and CD16 surface markers. An increase in the CD14++CD16- classical monocyte fraction ≥ 94% of the total monocytes was proposed to rapidly and efficiently distinguish chronic myelomonocytic leukemia from reactive monocytosis. The robustness of this assay required a multicenter validation. The flow cytometry assay designed to quantify peripheral blood monocyte subsets was implemented by multiple diagnosis laboratories in France. A nationwide survey was performed to evaluate its performance. All the 48 French laboratories answered the questionnaire, revealing that 63% use this assay routinely. Central blind reanalysis of 329 cytometry files collected from five laboratories demonstrated an excellent correlation in classical monocyte fraction measurement (r = 0.93; p < 0.0001). The cutoff value of 94% classical monocytes being the critical readout for diagnosis, we then compared 115 patients with classical monocytes ≥ 94% and 214 patients with a fraction < 94% between initial analysis and reanalysis. An agreement was obtained in 311 files. Finally, an overt diagnosis, available for 86 files, confirmed a good sensitivity (93.6%) and specificity (89.7%). This survey demonstrates the robustness of the flow assay with limited variability of classical monocyte percentage between centers, validates the 94% cutoff value, and confirms its sensitivity and specificity.
Assuntos
Citometria de Fluxo , Leucemia Mielomonocítica Crônica/diagnóstico , Leucemia Mielomonocítica Crônica/metabolismo , Monócitos/metabolismo , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Feminino , Citometria de Fluxo/métodos , França , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Curva ROC , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
Non-classical monocyte subsets may derive from classical monocyte differentiation and the proportion of each subset is tightly controlled. Deregulation of this repartition is observed in diverse human diseases, including chronic myelomonocytic leukemia (CMML) in which non-classical monocyte numbers are significantly decreased relative to healthy controls. Here, we identify a down-regulation of hsa-miR-150 through methylation of a lineage-specific promoter in CMML monocytes. Mir150 knock-out mice demonstrate a cell-autonomous defect in non-classical monocytes. Our pulldown experiments point to Ten-Eleven-Translocation-3 (TET3) mRNA as a hsa-miR-150 target in classical human monocytes. We show that Tet3 knockout mice generate an increased number of non-classical monocytes. Our results identify the miR-150/TET3 axis as being involved in the generation of non-classical monocytes.
Assuntos
Proteínas de Ligação a DNA/metabolismo , Dioxigenases/metabolismo , Leucemia Mielomonocítica Crônica/imunologia , MicroRNAs/metabolismo , Monócitos/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Animais , Metilação de DNA , Regulação para Baixo , Feminino , Regulação Leucêmica da Expressão Gênica , Humanos , Células K562 , Leucemia Mielomonocítica Crônica/metabolismo , Masculino , Camundongos , Camundongos Knockout , Cultura Primária de Células , Regiões Promotoras GenéticasRESUMO
Neutrophils represent the most abundant immune cells recruited to inflamed tissues. A lack of dedicated tools has hampered their detection and study. We show that a synthesized peptide, MUB40, binds to lactoferrin, the most abundant protein stored in neutrophil-specific and tertiary granules. Lactoferrin is specifically produced by neutrophils among other leukocytes, making MUB40 a specific neutrophil marker. Naive mammalian neutrophils (human, guinea pig, mouse, rabbit) were labeled by fluorescent MUB40 conjugates (-Cy5, Dylight405). A peptidase-resistant retro-inverso MUB40 (RI-MUB40) was synthesized and its lactoferrin-binding property validated. Neutrophil lactoferrin secretion during in vitro Shigella infection was assessed with RI-MUB40-Cy5 using live cell microscopy. Systemically administered RI-MUB40-Cy5 accumulated at sites of inflammation in a mouse arthritis inflammation model in vivo and showed usefulness as a potential tool for inflammation detection using non-invasive imaging. Improving neutrophil detection with the universal and specific MUB40 marker will aid the study of broad ranges of inflammatory diseases.
Assuntos
Carbocianinas/química , Corantes Fluorescentes/química , Inflamação/diagnóstico , Lactoferrina/análise , Neutrófilos/imunologia , Peptídeos/química , Adulto , Animais , Biomarcadores/análise , Disenteria Bacilar/complicações , Disenteria Bacilar/diagnóstico , Disenteria Bacilar/imunologia , Disenteria Bacilar/microbiologia , Feminino , Cobaias , Humanos , Inflamação/complicações , Inflamação/imunologia , Inflamação/microbiologia , Lactoferrina/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Neutrófilos/microbiologia , Coelhos , Shigella/imunologiaRESUMO
Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic disorder that associates dysplastic and proliferative features. Tissue inflammatory disorders occur in a fraction of CMML patients during the course of their disease. Here, we describe the occurrence of eosinophil-rich tissue inflammation, including eosinophilic pneumonia, chondritis, and cystitis, in CMML patients. Whole exome sequencing of leukemic cells did not identify a recurrent genetic abnormality among these three patients who were clinically improved by local or oral corticosteroids. Hypomethylating drugs were subsequently added in two of them, allowing decreasing corticosteroid doses and further treating their hematopoietic malignancy.
Assuntos
Eosinófilos/patologia , Leucemia Mielomonocítica Crônica/patologia , Infiltração Leucêmica , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Biomarcadores , Medula Óssea/patologia , Análise Citogenética , Eosinófilos/metabolismo , Evolução Fatal , Feminino , Humanos , Imunofenotipagem , Leucemia Mielomonocítica Crônica/diagnóstico , Leucemia Mielomonocítica Crônica/tratamento farmacológico , Leucemia Mielomonocítica Crônica/genética , Contagem de Leucócitos , Masculino , Mutação , Resultado do Tratamento , Sequenciamento do ExomaRESUMO
Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder that typically associates with mutations in epigenetic, splicing, and signaling genes. Genetically modified mouse models only partially recapitulate the disease phenotype, whereas xenotransplantation of CMML cells in immunocompromised mice has been rarely successful so far. Here, CMML CD34+ cells sorted from patient bone marrow (BM) or peripheral blood (PB) were injected intravenously into NSG (NOD/LtSz-scid IL2rγnull) mice and NSG mice engineered to express human granulo-monocyte colony-stimulating factor, stem cell factor, and interleukin-3 (NSGS mice). Fifteen out of 16 patient samples (94%) successfully engrafted into NSG or NSGS or both mouse strains. The expansion of human cells, predominant in the BM, was also observed in the spleen and the PB and was greatly enhanced in mice producing the 3 human cytokines. Gene mutations identified in engrafted cells were mostly similar to those identified in patient cells before injection. Successful secondary engraftment was obtained in NSGS mice in 3 out of 10 attempts. Thus, primary CMML leukemic cells expand much better in NSGS compared with NSG mice with limited efficacy of secondary transplant.
RESUMO
The cytidine analogues azacytidine and 5-aza-2'-deoxycytidine (decitabine) are commonly used to treat myelodysplastic syndromes, with or without a myeloproliferative component. It remains unclear whether the response to these hypomethylating agents results from a cytotoxic or an epigenetic effect. In this study, we address this question in chronic myelomonocytic leukaemia. We describe a comprehensive analysis of the mutational landscape of these tumours, combining whole-exome and whole-genome sequencing. We identify an average of 14±5 somatic mutations in coding sequences of sorted monocyte DNA and the signatures of three mutational processes. Serial sequencing demonstrates that the response to hypomethylating agents is associated with changes in DNA methylation and gene expression, without any decrease in the mutation allele burden, nor prevention of new genetic alteration occurence. Our findings indicate that cytosine analogues restore a balanced haematopoiesis without decreasing the size of the mutated clone, arguing for a predominantly epigenetic effect.
Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Azacitidina/análogos & derivados , Azacitidina/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Leucemia Mielomonocítica Crônica/genética , Mutação , Idoso , Idoso de 80 Anos ou mais , Alelos , Antimetabólitos Antineoplásicos/uso terapêutico , Azacitidina/uso terapêutico , Decitabina , Feminino , Células HEK293 , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucemia Mielomonocítica Crônica/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Análise de Sequência de DNA , Análise de Sequência de RNARESUMO
Autophagy is induced during differentiation of human monocytes into macrophages that is mediated by CSF1/CSF-1/M-CSF (colony stimulating factor 1 [macrophage]). However, little is known about the molecular mechanisms that link CSF1 receptor engagement to the induction of autophagy. Here we show that the CAMKK2-PRKAA1-ULK1 pathway is required for CSF1-induced autophagy and human monocyte differentiation. We reveal that this pathway links P2RY6 to the induction of autophagy, and we decipher the signaling network that links the CSF1 receptor to P2RY6-mediated autophagy and monocyte differentiation. In addition, we show that the physiological P2RY6 ligand UDP and the specific P2RY6 agonist MRS2693 can restore normal monocyte differentiation through reinduction of autophagy in primary myeloid cells from some but not all chronic myelomonocytic leukemia (CMML) patients. Collectively, our findings highlight an essential role for PRKAA1-mediated autophagy during differentiation of human monocytes and pave the way for future therapeutic interventions for CMML.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Autofagia/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Leucemia Mieloide/patologia , Fator Estimulador de Colônias de Macrófagos/farmacologia , Monócitos/citologia , Transdução de Sinais/efeitos dos fármacos , Animais , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/metabolismo , Linhagem Celular Tumoral , Ativação Enzimática/efeitos dos fármacos , Humanos , Leucemia Mieloide/enzimologia , Camundongos Endogâmicos C57BL , Modelos Biológicos , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Fosfolipase C gama/metabolismo , Receptores Purinérgicos P2/metabolismo , Difosfato de Uridina/farmacologiaRESUMO
Myelodysplastic syndromes and chronic myelomonocytic leukemia (CMML) are characterized by mutations in genes encoding epigenetic modifiers and aberrant DNA methylation. DNA methyltransferase inhibitors (DMTis) are used to treat these disorders, but response is highly variable, with few means to predict which patients will benefit. Here, we examined baseline differences in mutations, DNA methylation, and gene expression in 40 CMML patients who were responsive or resistant to decitabine (DAC) in order to develop a molecular means of predicting response at diagnosis. While somatic mutations did not differentiate responders from nonresponders, we identified 167 differentially methylated regions (DMRs) of DNA at baseline that distinguished responders from nonresponders using next-generation sequencing. These DMRs were primarily localized to nonpromoter regions and overlapped with distal regulatory enhancers. Using the methylation profiles, we developed an epigenetic classifier that accurately predicted DAC response at the time of diagnosis. Transcriptional analysis revealed differences in gene expression at diagnosis between responders and nonresponders. In responders, the upregulated genes included those that are associated with the cell cycle, potentially contributing to effective DAC incorporation. Treatment with CXCL4 and CXCL7, which were overexpressed in nonresponders, blocked DAC effects in isolated normal CD34+ and primary CMML cells, suggesting that their upregulation contributes to primary DAC resistance.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Azacitidina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/genética , Genes Neoplásicos , Leucemia Mielomonocítica Crônica/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/farmacologia , Azacitidina/farmacologia , Azacitidina/uso terapêutico , Medula Óssea/patologia , Metilação de DNA/efeitos dos fármacos , Análise Mutacional de DNA , DNA Intergênico/genética , Decitabina , Elementos Facilitadores Genéticos/genética , Feminino , Humanos , Leucemia Mielomonocítica Crônica/genética , Leucemia Mielomonocítica Crônica/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Fator Plaquetário 4/biossíntese , Fator Plaquetário 4/genética , Fator Plaquetário 4/fisiologia , Resultado do Tratamento , beta-Tromboglobulina/biossíntese , beta-Tromboglobulina/genética , beta-Tromboglobulina/fisiologiaRESUMO
Chronic myelomonocytic leukemia is a clonal malignancy of the ageing hematopoietic stem cell characterized by a biased differentiation leading to persistent monocytosis and inconstant hypersensitivity of myeloid progenitors to granulo-monocyte colony-stimulating factor (GM-CSF). Cytogenetic abnormalities identified in 30-40 % of patients and gene mutations detected in every patient can be used to stratify patients into risk groups that guide the therapeutic choices. TET2, SRSF2, ASXL1, and genes of the Ras pathway are the most frequently mutated genes, with ASXL1 mutations negatively affecting the disease outcome. Allogeneic stem cell transplantation is the first option to consider, especially in younger patients with poor prognostic factors. There is no firm clinical guideline in transplant-ineligible patients, but hypomethylating agents might be an interesting option. A consensus prognostic scoring system and specific response criteria are now required to facilitate the evaluation of new therapeutic strategies in clinical trials specifically dedicated to this disease.