RESUMEN
Chronic myelomonocytic leukemia (CMML) is a rare and challenging type of myeloproliferative neoplasm. Poor prognosis and high mortality, associated predominantly with progression to secondary acute myeloid leukemia (sAML), is still an unsolved problem. Despite a growing body of knowledge about the molecular repertoire of this disease, at present, the prognostic significance of CMML-associated mutations is controversial. The absence of available CMML cell lines and the small number of patients with CMML make pre-clinical testing and clinical trials complicated. Currently, specific therapy for CMML has not been approved; most of the currently available therapeutic approaches are based on myelodysplastic syndrome (MDS) and other myeloproliferative neoplasm (MNP) studies. In this regard, the development of the robust CMML animal models is currently the focus of interest. This review describes important studies concerning animal models of CMML, examples of methodological approaches, and the obtained hematologic phenotypes.
Asunto(s)
Leucemia Mielomonocítica Crónica/etiología , Animales , Epigénesis Genética , Xenoinjertos , Humanos , Leucemia Experimental/etiología , Leucemia Experimental/genética , Leucemia Experimental/terapia , Leucemia Mielomonocítica Crónica/genética , Leucemia Mielomonocítica Crónica/terapia , Ratones , Mutación , Oncogenes , FenotipoRESUMEN
Background: Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) are associated with cutaneous manifestations. Next-generation sequencing (NGS) is a tool capable of identifying clonal myeloid cells in the skin infiltrate and thus better characterize the link between hematological diseases and skin lesions. Objective: To assess whether skin lesions of MDS/CMML are clonally related to blood or bone marrow cells using NGS. Methods: Comparisons of blood or bone marrow and skin samples NGS findings from patients presenting with MDS/CMML and skin lesions in three French hospitals. Results: Among the 14 patients recruited, 12 patients (86%) had mutations in the skin lesions biopsied, 12 patients (86%) had a globally similar mutational profile between blood/bone marrow and skin, and 10 patients (71%) had mutations with a high variant allele frequency (>10%) found in the myeloid skin infiltrate. Mutations in TET2 and DNMT3A, both in four patients, were the most frequent. Two patients harbored a UBA1 mutation on hematopoietic samples. Limitations: Limited number of patients and retrospective collection of the data. Blood and skin sampling were not performed at the exact same time point for two patients. Conclusion: Skin lesions in the setting of MDS/CMML are characterized by a clonal myeloid infiltrate in most cases.
Asunto(s)
Leucemia Mielomonocítica Crónica/complicaciones , Leucemia Mielomonocítica Crónica/patología , Síndromes Mielodisplásicos/complicaciones , Síndromes Mielodisplásicos/patología , Células Mieloides/patología , Enfermedades de la Piel/diagnóstico , Enfermedades de la Piel/etiología , Anciano , Anciano de 80 o más Años , Biopsia , Médula Ósea/patología , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/patología , Evolución Clonal/genética , Manejo de la Enfermedad , Femenino , Perfilación de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Leucemia Mielomonocítica Crónica/etiología , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/etiología , Evaluación de SíntomasRESUMEN
PURPOSE: Chronic myelomonocytic leukemia (CMML) is a rare leukemia characterized by peripheral monocytosis with no disease-modifying therapies. CMML cells are uniquely hypersensitive to granulocyte-macrophage colony-stimulating factor (GM-CSF) and robustly engraft in immunocompromised mice that secrete human cytokines. To leverage these unique biological features, we conducted an integrated human and murine study evaluating ruxolitinib, a JAK1/2 inhibitor that potently downregulates intracellular GM-CSF signaling. PATIENTS AND METHODS: A total of 50 patients with WHO-defined CMML were enrolled in this open-label, multi-institution phase I/II clinical study, with a ruxolitinib dose of 20 mg twice daily studied in phase II. In parallel, 49 patient-derived xenografts (PDX) derived from 13 study participants were generated and randomized to receive ruxolitinib or vehicle control. RESULTS: The most common grade 3/4 treatment-related toxicities observed were anemia (10%) and thrombocytopenia (6%). The clinical overall response rate was 38% by Myelodysplastic Syndrome/Myeloproliferative Neoplasm (MDS/MPN) International Working Group (IWG) criteria and 43% of patients with baseline splenomegaly achieved a spleen response. Profiling of cytokine levels and somatic mutations at baseline failed to identify predictive biomarkers. PDX models derived from screening samples of study participants recapitulated responses seen in humans, particularly spleen responses, and corroborated ruxolitinib's clinical efficacy in a randomized murine study not feasible in human trials. CONCLUSIONS: Ruxolitinib demonstrated clinical efficacy and an acceptable adverse event profile in patients with CMML, identifying a potential novel therapeutic in this rare malignancy. Furthermore, this study demonstrates proof of concept that PDX modeling can recapitulate responses of patients treated on clinical trial and represents a novel correlative study that corroborates clinical efficacy seen in humans.See related commentary by Shastri and Adrianzen-Herrera, p. 6069.
Asunto(s)
Inhibidores de las Cinasas Janus/farmacología , Inhibidores de las Cinasas Janus/uso terapéutico , Leucemia Mielomonocítica Crónica/tratamiento farmacológico , Nitrilos/farmacología , Nitrilos/uso terapéutico , Pirazoles/farmacología , Pirazoles/uso terapéutico , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Animales , Biomarcadores de Tumor , Ensayos Clínicos como Asunto , Citocinas/sangre , Citocinas/genética , Citocinas/metabolismo , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Leucemia Mielomonocítica Crónica/diagnóstico , Leucemia Mielomonocítica Crónica/etiología , Leucemia Mielomonocítica Crónica/mortalidad , Masculino , Ratones , Persona de Mediana Edad , Mutación , Pronóstico , Resultado del TratamientoRESUMEN
In older patients with chronic myelomonocytic leukaemia (CMML) and limited life expectancy due to age and or comorbidities, it is particularly important to consider the risk of transformation for individualised treatment decisions. There is limited information on potential differences between younger and older CMML patients regarding the cumulative risk of transformation as well as haematological, molecular and biologic characteristics. We analysed data from the Austrian Biodatabase for CMML (ABCMML) to compare these parameters in 518 CMML patients. Categorisation of patients into 3 age-related groups: <60 years, 60-79 years and ≥80 years, showed a significantly lower risk of transformation at higher age by competing risk analysis, with a 4-year risk of 39%, 23% and 13%, respectively (P < .0001). The lower probability of transformation was associated with a lower percentage of blast cells in the peripheral blood (PB) of older patients. Furthermore, we provide a simple score based on age, PB blasts and platelet counts that allowed us to define subgroups of CMML patients with a different cumulative transformation risk, including a low-risk group with a transformation risk of only 5%. Our findings may facilitate reasonable treatment decisions in elderly patients with CMML.
Asunto(s)
Evaluación del Impacto en la Salud , Leucemia Mielomonocítica Crónica/epidemiología , Leucemia Mielomonocítica Crónica/patología , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor , Comorbilidad , Progresión de la Enfermedad , Susceptibilidad a Enfermedades , Femenino , Humanos , Leucemia Mielomonocítica Crónica/etiología , Leucemia Mielomonocítica Crónica/mortalidad , Masculino , Persona de Mediana Edad , Oportunidad Relativa , PronósticoRESUMEN
PURPOSE OF REVIEW: Monocytosis is a distinct but non-specific manifestation of various physiologic and pathologic conditions. Among hematopoietic stem cell neoplasms, depending on the criteria used for disease classification, monocytosis may be a consistent and integral component of diseases such as chronic myelomonocytic leukemia or acute myeloid leukemia with monocytic differentiation, or it may represent an inconsistent finding that often provides a clue to the underlying genetic changes driving the neoplasm. The purpose of this review is to provide the readers with a laboratory-based approach to neoplastic monocytosis. RECENT FINDINGS: In-depth elucidation of the genomic landscape of myeloid neoplasms within the past few years has broadened our understanding of monocytosis and its implications for diagnosis and prognosis. Genetic findings also shed light on potential disease response - or lack thereof - to various therapeutic agents used in the setting of myeloid neoplasms. In this review, we provide our approach to diagnose neoplastic monocytosis in the context of case-based studies while incorporating the most recent literature on this topic.
Asunto(s)
Leucemia Mieloide/diagnóstico , Leucemia Mielomonocítica Crónica/diagnóstico , Factores de Edad , Biomarcadores , Médula Ósea/patología , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Manejo de la Enfermedad , Progresión de la Enfermedad , Susceptibilidad a Enfermedades , Predisposición Genética a la Enfermedad , Variación Genética , Humanos , Leucemia Mieloide/etiología , Leucemia Mieloide/mortalidad , Leucemia Mielomonocítica Crónica/etiología , Leucemia Mielomonocítica Crónica/mortalidad , Monocitos/metabolismo , Monocitos/patologíaRESUMEN
PURPOSE OF REVIEW: For decades, the management of chronic myelomonocytic leukemia (CMML) or juvenile myelomonocytic leukemia (JMML) has been largely inextricable from myelodysplastic syndromes (MDS), myeloproliferative neoplasms, and acute myeloid leukemia. Hallmarks of these diseases have been the emergence of unique genomic signatures and discouraging responses to available therapies. Here, we will critically examine the current options for management and review the rapidly developing opportunities based on advances in CMML and JMML disease biology. RECENT FINDINGS: Few clinical trials have exclusively been done in CMML, and in JMML, the rarity of the disease limits wide scale participation. Recent case series in JMML suggest that hypomethylating agents (HMAs) are a viable option for bridging to curative intent with allogeneic hematopoietic stem cell transplant or as posttransplant maintenance. Emerging evidence has demonstrated targeting the RAS-pathway via MEK inhibition may also be considered. In CMML, treatment with HMAs is largely derived from data inclusive of MDS patients, including a small number of patients with dysplastic CMML variants. Based on CMML disease biology, additional therapeutic targets being investigated include inhibitors of splicing, CD123/dendritic cell axis, inherent GM-CSF progenitor cell hypersensitivity, and targeting the JAK/STAT pathway. Current evidence is also expanding for oral HMAs. The management of CMML and JMML is rapidly evolving and clinicians must be aware of the genetic landscape and expanding treatment options to ensure these rare populations are afforded therapeutic interventions best suited to their needs.
Asunto(s)
Leucemia Mieloide/terapia , Leucemia Mielomonocítica Juvenil/terapia , Factores de Edad , Biomarcadores , Terapia Combinada , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Trasplante de Células Madre Hematopoyéticas , Humanos , Leucemia Mieloide/diagnóstico , Leucemia Mieloide/etiología , Leucemia Mielomonocítica Crónica/diagnóstico , Leucemia Mielomonocítica Crónica/etiología , Leucemia Mielomonocítica Crónica/terapia , Leucemia Mielomonocítica Juvenil/diagnóstico , Leucemia Mielomonocítica Juvenil/etiología , Terapia Molecular DirigidaRESUMEN
Chronic myelomonocytic leukemia is a clonal chronic hematopoietic disorder that has been classified under the category of Myelodysplastic syndrome/Myeloproliferative neoplasms (MDS/MPN). CMML has high chances of transforming to acute leukemia, however isolated CNS relapse in CMML has never been reported in literature. We report an extremely rare case of a 47 yearold female diagnosed to have CMML- 2 in remission, who developed an isolated central nervous system relapse after matched related allogeneic hematopoietic stem cell transplantation. To our knowledge this is the first report of isolated CNS relapse in CMML post allogeneic stem cell transplant.
Asunto(s)
Sistema Nervioso Central/patología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Leucemia Mielomonocítica Crónica/diagnóstico , Leucemia Mielomonocítica Crónica/genética , Mutación , Tirosina Quinasa 3 Similar a fms/genética , Enfermedad Aguda , Femenino , Humanos , Leucemia Mielomonocítica Crónica/etiología , Persona de Mediana Edad , RecurrenciaRESUMEN
BACKGROUND: Myelomonocytic skewing is considered as a key pathophysiologic phenomenon in chronic myelomonocytic leukemia (CMML), but its prevalence and potential correlation with phenotypic, genotypic, and clinical features are poorly defined. METHODS: Skewed differentiation toward the myelomonocytic over erythroid commitment as indicated by an inverse ratio of myelomonocytic/erythroid colonies was investigated in 146 patients with CMML by semisolid in vitro cultures. RESULTS: There was a high prevalence of myelomonocytic skewing in patients with CMML (120/146, 82%); whereas, this phenomenon was rare in normal individuals (1/98, 1%). Patients with CMML with myelomonocytic skewing had higher white blood cell and peripheral blast cell counts, and lower platelet values. The number of mutations in genes of the epigenetic and/or splicing category was higher in CMML patients with as compared with patients without skewing. Patients with myelomonocytic skewing had more frequently mutations in RASopathy genes and higher growth factor independent myeloid colony formation. Interestingly, the lack of myelomonocytic skewing discriminated patients with CMML with a particularly favorable prognosis (60 vs 19 months, P = .003) and a minimal risk of transformation. CONCLUSION: Myelomonocytic skewing as determined by semisolid cultures can discriminate subgroups of patients with CMML with a different phenotype, a different genotype, and a different prognosis.
Asunto(s)
Leucemia Mielomonocítica Crónica/diagnóstico , Leucemia Mielomonocítica Crónica/mortalidad , Recuento de Leucocitos , Leucocitos Mononucleares/patología , Células Mieloides/patología , Biomarcadores , Biomarcadores de Tumor , Progresión de la Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Leucemia Mielomonocítica Crónica/etiología , Leucocitos Mononucleares/metabolismo , Masculino , Mutación , Células Mieloides/metabolismo , Fenotipo , Pronóstico , Transducción de Señal , Proteínas ras/genética , Proteínas ras/metabolismoRESUMEN
Hematolymphoid neoplasms, including lymphoma and myeloid neoplasms, can occur in patients with sickle cell disease (SCD) or equivalent hemoglobinopathy, but an underlying connection between the two conditions has yet to be fully determined. Herein, we report a unique case of sequential development of two separate hematolymphoid neoplasms, human herpes virus 8 (HHV8)-positive diffuse large B-cell lymphoma (DLBCL) and chronic myelomonocytic leukemia, in a 59â¯year-old African American female with hemoglobin SC disease. While etiology of immunodeficiency is unknown, the potential causes include hydroxyurea therapy, disease related immunomodulation, chronic inflammation, and relatively old age. The leukemia cells demonstrated profound trilineage dysplasia and harbored complex cytogenetic abnormalities with loss of chromosome 5q and 7q, which are often observed in therapy-related myeloid neoplasms. Besides the potential causes listed above, we propose that myeloid leukemia in this setting may result from genomic changes due to excessive hematopoietic replication triggered by a hemolysis-induced cytokine storm. While myeloid neoplasms in the setting of SCD seems to herald a dismal clinical outcome per the literature, the HHV8-positive DLBCL in our case was apparently indolent, opposing the current perception of its clinical outcome.
Asunto(s)
Enfermedad de la Hemoglobina SC/complicaciones , Infecciones por Herpesviridae/virología , Herpesvirus Humano 8/patogenicidad , Leucemia Mielomonocítica Crónica/etiología , Linfoma de Células B Grandes Difuso/etiología , Antidrepanocíticos/efectos adversos , Transformación Celular Neoplásica/genética , Progresión de la Enfermedad , Resultado Fatal , Femenino , Enfermedad de la Hemoglobina SC/diagnóstico , Enfermedad de la Hemoglobina SC/tratamiento farmacológico , Enfermedad de la Hemoglobina SC/genética , Infecciones por Herpesviridae/complicaciones , Infecciones por Herpesviridae/diagnóstico , Humanos , Hidroxiurea/efectos adversos , Leucemia Mielomonocítica Crónica/diagnóstico , Leucemia Mielomonocítica Crónica/genética , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/virología , Persona de Mediana Edad , Factores de RiesgoRESUMEN
Chronic myelomonocytic leukemia (CMML) constitutes a hematopoietic stem cell (HSC) disorder characterized by prominent monocytosis and myelodysplasia. Although genome sequencing has revealed the CMML mutation profile, the mechanism of disease development remains unclear. Here we show that aberrant histone acetylation by nucleoporin-98 (NUP98)-HBO1, a newly identified fusion in a patient with CMML, is sufficient to generate clinically relevant CMML pathogenesis. Overexpression of NUP98-HBO1 in murine HSC/progenitors (HSC/Ps) induced diverse CMML phenotypes, such as severe leukocytosis, increased CD115+ Ly6Chigh monocytes (an equivalent subpopulation to human classical CD14+ CD16- monocytes), macrocytic anemia, thrombocytopenia, megakaryocyte-lineage dysplasia, splenomegaly, and cachexia. A NUP98-HBO1-mediated transcriptional signature in human CD34+ cells was specifically activated in HSC/Ps from a CMML patient cohort. Besides critical determinants of monocytic cell fate choice in HSC/Ps, an oncogenic HOXA9 signature was significantly activated by NUP98-HBO1 fusion through aberrant histone acetylation. Increased HOXA9 gene expression level with disease progression was confirmed in our CMML cohort. Genetic disruption of NUP98-HBO1 histone acetyltransferase activity abrogated its leukemogenic potential and disease development in human cells and a mouse model. Furthermore, treatment of azacytidine was effective in our CMML mice. The recapitulation of CMML clinical phenotypes and gene expression profile by the HBO1 fusion suggests our new model as a useful platform for elucidating the central downstream mediators underlying diverse CMML-related mutations and testing multiple compounds, providing novel therapeutic potential.
Asunto(s)
Histona Acetiltransferasas/genética , Leucemia Mielomonocítica Crónica/etiología , Proteínas de Complejo Poro Nuclear/genética , Proteínas de Fusión Oncogénica/genética , Acetilación , Animales , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Histonas/metabolismo , Proteínas de Homeodominio/metabolismo , Humanos , Leucemia Mielomonocítica Crónica/patología , Ratones , FenotipoRESUMEN
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.
Asunto(s)
Enfermedades Autoinmunes/complicaciones , Síndromes Mielodisplásicos/complicaciones , Síndromes Mielodisplásicos/epidemiología , Adulto , Anciano , Anciano de 80 o más Años , Enfermedades Autoinmunes/diagnóstico , Enfermedades Autoinmunes/epidemiología , Enfermedades Autoinmunes/inmunología , Biomarcadores , Femenino , Humanos , Incidencia , Leucemia Mielomonocítica Crónica/epidemiología , Leucemia Mielomonocítica Crónica/etiología , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/diagnóstico , Evaluación del Resultado de la Atención al Paciente , Prevalencia , Pronóstico , Adulto JovenRESUMEN
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.
Asunto(s)
Histona Demetilasas/genética , Leucemia Mielomonocítica Crónica/etiología , Mutación , Animales , Diferenciación Celular , Linaje de la Célula , Genes p53 , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/fisiología , Histona Demetilasas/fisiología , Histonas/metabolismo , Ratones , Ratones NoqueadosRESUMEN
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.
Asunto(s)
Metilación de ADN , Leucemia Mielomonocítica Crónica/genética , Leucemia Mielomonocítica Crónica/mortalidad , Anciano , Estudios de Casos y Controles , Proteínas de Unión al ADN/genética , Dioxigenasas , Supervivencia sin Enfermedad , Epigénesis Genética , Femenino , Regulación Leucémica de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Leucemia Mielomonocítica Crónica/etiología , Masculino , Mutación , Análisis de Secuencia por Matrices de Oligonucleótidos , Pronóstico , Proteínas Proto-Oncogénicas/genéticaRESUMEN
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.
Asunto(s)
Transformación Celular Neoplásica/genética , Reordenamiento Génico , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/complicaciones , Leucemia Mielomonocítica Crónica/patología , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/genética , Adulto , Transformación Celular Neoplásica/patología , Progresión de la Enfermedad , Humanos , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/genética , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/patología , Leucemia Mielomonocítica Crónica/etiología , Masculino , PronósticoRESUMEN
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.
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Leucemia Mieloide Aguda/etiología , Leucemia Mielomonocítica Crónica/etiología , Mieloma Múltiple/patología , Mieloma Múltiple/terapia , Síndromes Mielodisplásicos/etiología , Neoplasias Primarias Secundarias/etiología , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
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.
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Benceno/efectos adversos , Carcinógenos Ambientales/efectos adversos , Leucemia Mielomonocítica Crónica/etiología , Exposición Profesional/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , China , Exposición a Riesgos Ambientales/efectos adversos , Exposición a Riesgos Ambientales/estadística & datos numéricos , Femenino , Humanos , Hibridación Fluorescente in Situ , Leucemia Mielomonocítica Crónica/diagnóstico , Leucemia Mielomonocítica Crónica/genética , Masculino , Persona de Mediana Edad , Exposición Profesional/estadística & datos numéricos , Oportunidad Relativa , Estudios Prospectivos , Factores de Riesgo , Encuestas y CuestionariosRESUMEN
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.
Asunto(s)
Trastornos de las Plaquetas Sanguíneas/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Predisposición Genética a la Enfermedad , Leucemia Mieloide Aguda/genética , Leucemia Mielomonocítica Crónica/etiología , Mutación/genética , Proteínas Proto-Oncogénicas c-cbl/genética , Adulto , Trastornos de las Plaquetas Sanguíneas/complicaciones , Niño , Cromosomas Humanos Par 11/genética , Femenino , Genes Dominantes , Haplotipos/genética , Humanos , Immunoblotting , Leucemia Mieloide Aguda/complicaciones , Masculino , Persona de Mediana Edad , Linaje , Reacción en Cadena de la PolimerasaRESUMEN
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.