RESUMO
Descriptive epidemiological information on myeloproliferative neoplasms (MPNs) and myelodysplastic (MDS)/MPNs is largely derived from single institution and European population-based studies. Data obtained following adoption of the World Health Organization classification of haematopoietic neoplasms and JAK2 V617F mutation testing are sparse. Using population-based data, we comprehensively assessed subtype-specific MPN and MDS/MPN incidence rates (IRs), IR ratios (IRRs) and relative survival (RS) in the United States (2001-12). IRs were highest for polycythaemia vera (PV) (IR = 10·9) and essential thrombocythaemia (ET) (IR = 9·6). Except for ET and mastocytosis, overall IRs were significantly higher among males (IRRs = 1·4-2·3). All evaluable MPNs were associated with lower IRs among Hispanic whites than non-Hispanic whites (NHWs), with the exception of BCR-ABL1-positive chronic myeloid leukaemia (CML), chronic eosinophilic leukaemia (CEL) and juvenile myelomonocytic leukaemia. Except for CEL, Asians/Pacific Islanders had significantly lower MPN IRs than NHWs. ET, MPN-unclassifiable and CEL IRs were 18%, 19% and 60% higher, respectively, among blacks than NHWs. Five-year RS was more favourable for younger (<60 years) than older individuals and for women compared with men, except for PV at older ages. RS was highest (>90%) for younger PV and ET patients and lowest (<20%) for older chronic myelomonocytic leukaemia and atypical BCR-ABL1-negative CML patients. Varying MPN and MDS/MPN incidence patterns by subtype support distinct aetiologies and/or susceptible populations. Decreased survival rates as compared to that expected in the general population were associated with every MPN subtype, highlighting the need for new treatments, particularly among older individuals.
Assuntos
Doenças Mieloproliferativas-Mielodisplásicas/epidemiologia , Transtornos Mieloproliferativos/epidemiologia , Fatores Etários , Idoso , Etnicidade , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Doenças Mieloproliferativas-Mielodisplásicas/classificação , Doenças Mieloproliferativas-Mielodisplásicas/mortalidade , Transtornos Mieloproliferativos/classificação , Transtornos Mieloproliferativos/mortalidade , Fatores Sexuais , Análise de Sobrevida , Estados Unidos/epidemiologiaRESUMO
Our knowledge of the genetic basis of myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) has considerably improved. To define genotype/phenotype relationships of clinical relevance, we studied 308 patients with MDS, MDS/MPN, or acute myeloid leukemia evolving from MDS. Unsupervised statistical analysis, including the World Health Organization classification criteria and somatic mutations, showed that MDS associated with SF3B1-mutation (51 of 245 patients, 20.8%) is a distinct nosologic entity irrespective of current morphologic classification criteria. Conversely, MDS with ring sideroblasts with nonmutated SF3B1 segregated in different clusters with other MDS subtypes. Mutations of genes involved in DNA methylation, splicing factors other than SF3B1, and genes of the RAS pathway and cohesin complex were independently associated with multilineage dysplasia and identified a distinct subset (51 of 245 patients, 20.8%). No recurrent mutation pattern correlated with unilineage dysplasia without ring sideroblasts. Irrespective of driver somatic mutations, a threshold of 5% bone marrow blasts retained a significant discriminant value for identifying cases with clonal evolution. Comutation of TET2 and SRSF2 was highly predictive of a myeloid neoplasm characterized by myelodysplasia and monocytosis, including but not limited to, chronic myelomonocytic leukemia. These results serve as a proof of concept that a molecular classification of myeloid neoplasms is feasible.
Assuntos
Leucemia Mieloide Aguda/genética , Mutação , Síndromes Mielodisplásicas/genética , Doenças Mieloproliferativas-Mielodisplásicas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas de Ciclo Celular/genética , Proteínas Cromossômicas não Histona/genética , Estudos de Coortes , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Metilação de DNA/genética , Feminino , Genes ras , Estudos de Associação Genética , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/classificação , Síndromes Mielodisplásicas/patologia , Doenças Mieloproliferativas-Mielodisplásicas/classificação , Doenças Mieloproliferativas-Mielodisplásicas/patologia , Células Mieloides/patologia , Fosfoproteínas/genética , Prognóstico , Fatores de Processamento de RNA , Ribonucleoproteína Nuclear Pequena U2/genética , CoesinasRESUMO
PURPOSE OF REVIEW: This article will review the most recent advances in the understanding of the genetic basis of myeloid neoplasms with myelodysplasia and will discuss its clinical implications. RECENT FINDINGS: Recurrent somatic mutations have been identified in about 90% of patients with myeloid neoplasms with myelodysplasia, involving genes of RNA splicing, DNA methylation, histone modification, transcription regulation, DNA repair, signal transduction, and cohesin complex. Somatic mutations are acquired in a linear manner in a multipotent hematopoietic stem cell, resulting in a growth advantage at the stem cell level and in defective differentiation and maturation of hematopoietic precursors. Recently, evidence has been provided of age-related hematopoietic clones, driven by mutations of genes recurrently mutated in myeloid neoplasms. These hematopoietic clones may represent either premalignant clones with the potential to progress to myeloid neoplasm or small malignant clones at a preclinical stage. SUMMARY: The available evidence clearly indicates that greater understanding of the molecular basis of myeloid neoplasms with myelodysplasia has relevant implications in the classification of these disorders, as well as in predicting disease risk and response to specific treatment modalities, and may open avenues of research leading to novel therapeutic options and personalized treatment in the individual patient.
Assuntos
Síndromes Mielodisplásicas/genética , Doenças Mieloproliferativas-Mielodisplásicas/genética , Metilação de DNA/genética , Epigenômica , Genômica , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , Hematopoese/genética , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Mutação , Síndromes Mielodisplásicas/patologia , Doenças Mieloproliferativas-Mielodisplásicas/classificação , Doenças Mieloproliferativas-Mielodisplásicas/patologiaAssuntos
Mutação , Doenças Mieloproliferativas-Mielodisplásicas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Mutação , Doenças Mieloproliferativas-Mielodisplásicas/classificação , Neoplasias/classificação , Neoplasias/genética , Análise de Sobrevida , Adulto JovemAssuntos
Mutação , Doenças Mieloproliferativas-Mielodisplásicas/classificação , Transtornos Mieloproliferativos/classificação , Proteínas de Neoplasias/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Mieloproliferativas-Mielodisplásicas/diagnóstico , Doenças Mieloproliferativas-Mielodisplásicas/genética , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/genética , Adulto JovemRESUMO
Changing definitions and classifications of hematologic malignancies (HMs) complicate incidence comparisons. HAEMACARE classified HMs into groupings consistent with the latest World Health Organization classification and useful for epidemiologic and public health purposes. We present crude, age-specific and age-standardized incidence rates for European HMs according to these groupings, estimated from 66,371 lymphoid malignancies (LMs) and 21,796 myeloid malignancies (MMs) registered in 2000-2002 by 44 European cancer registries, grouped into 5 regions. Age-standardized incidence rates were 24.5 (per 100,000) for LMs and 7.55 for MMs. The commonest LMs were plasma cell neoplasms (4.62), small B-cell lymphocytic lymphoma/chronic lymphatic leukemia (3.79), diffuse B-cell lymphoma (3.13), and Hodgkin lymphoma (2.41). The commonest MMs were acute myeloid leukemia (2.96), other myeloproliferative neoplasms (1.76), and myelodysplastic syndrome (1.24). Unknown morphology LMs were commonest in Northern Europe (7.53); unknown morphology MMs were commonest in Southern Europe (0.73). Overall incidence was lowest in Eastern Europe and lower in women than in men. For most LMs, incidence was highest in Southern Europe; for MMs incidence was highest in the United Kingdom and Ireland. Differences in diagnostic and registration criteria are an important cause of incidence variation; however, different distribution of HM risk factors also contributes. The quality of population-based HM data needs further improvement.
Assuntos
Neoplasias Hematológicas/epidemiologia , Europa (Continente)/epidemiologia , Feminino , Neoplasias Hematológicas/classificação , Humanos , Incidência , Leucemia/classificação , Leucemia/epidemiologia , Linfoma/classificação , Linfoma/epidemiologia , Masculino , Doenças Mieloproliferativas-Mielodisplásicas/classificação , Doenças Mieloproliferativas-Mielodisplásicas/epidemiologia , Sistema de RegistrosAssuntos
Calreticulina/genética , Mutação , Doenças Mieloproliferativas-Mielodisplásicas/genética , Transtornos Mieloproliferativos/genética , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Mieloproliferativas-Mielodisplásicas/classificação , Doenças Mieloproliferativas-Mielodisplásicas/patologia , Transtornos Mieloproliferativos/classificação , Transtornos Mieloproliferativos/patologiaRESUMO
Mastocytosis and myeloid eosinophilic neoplasms are rare diseases of the bone marrow and are often a diagnostic challenge for hematopathologists. In mastocytosis, compact mast cell infiltrates represent the main diagnostic criterion and for myeloid eosinophilic neoplasms, eosinophilic granulocytes dominate the histological picture. Both disease groups include phenotypically and prognostically very different entities which are each defined by WHO criteria. For systemic mastocytosis (SM), a differentiation between indolent and aggressive or even leukemic forms is of prognostic importance. In indolent variants of SM, a local and/or systemic, usually reactive increase in eosinophilic granulocytes (SM-eo) is often observed. In contrast, an increase in neoplastic eosinophils is often observed in advanced SM, predominantly in diseases designated SM with associated non-mastocytic hematological neoplasms (SM-AHNMD), e.g. in SM with chronic eosinophilic leukemia (SM-CEL). Apart from mastocytoses, immunophenotypically aberrant tissue mast cells are only observed in certain rare forms of myeloid neoplasms with eosinophilia, in particular in myeloproliferative neoplasms (MPN-eo) with cytogenic anomalies in the platelet-derived growth factor receptor (PDGFR). The World Health Organization (WHO) classification of eosinophilic leukemias, however, fulfils the morphological and clinical requirements in a limited way only and needs an update.
Assuntos
Síndrome Hipereosinofílica/classificação , Síndrome Hipereosinofílica/diagnóstico , Mastocitose Sistêmica/classificação , Mastocitose Sistêmica/diagnóstico , Mastocitose/classificação , Mastocitose/diagnóstico , Biópsia por Agulha , Medula Óssea/patologia , Coristoma/patologia , Análise Citogenética , Diagnóstico Diferencial , Eosinófilos/patologia , Síndrome Hipereosinofílica/genética , Síndrome Hipereosinofílica/patologia , Imunofenotipagem , Leucemia de Mastócitos/classificação , Leucemia de Mastócitos/diagnóstico , Leucemia de Mastócitos/genética , Leucemia de Mastócitos/patologia , Mastócitos/patologia , Mastocitose/genética , Mastocitose/patologia , Mastocitose Sistêmica/genética , Mastocitose Sistêmica/patologia , Doenças Mieloproliferativas-Mielodisplásicas/classificação , Doenças Mieloproliferativas-Mielodisplásicas/diagnóstico , Doenças Mieloproliferativas-Mielodisplásicas/genética , Doenças Mieloproliferativas-Mielodisplásicas/patologia , Prognóstico , Receptores do Fator de Crescimento Derivado de Plaquetas/genéticaRESUMO
Recently the World Health Organization (WHO), in collaboration with the European Association for Haematopathology and the Society for Hematopathology, published a revised and updated edition of the WHO Classification of Tumors of the Hematopoietic and Lymphoid Tissues. The 4th edition of the WHO classification incorporates new information that has emerged from scientific and clinical studies in the interval since the publication of the 3rd edition in 2001, and includes new criteria for the recognition of some previously described neoplasms as well as clarification and refinement of the defining criteria for others. It also adds entities-some defined principally by genetic features-that have only recently been characterized. In this paper, the classification of myeloid neoplasms and acute leukemia is highlighted with the aim of familiarizing hematologists, clinical scientists, and hematopathologists not only with the major changes in the classification but also with the rationale for those changes.
Assuntos
Leucemia/classificação , Síndromes Mielodisplásicas/classificação , Transtornos Mieloproliferativos/classificação , Doença Aguda , Exame de Medula Óssea/normas , Contagem de Células , Linhagem da Célula , Aberrações Cromossômicas , Eosinofilia/classificação , Neoplasias Hematológicas/classificação , Humanos , Leucemia/diagnóstico , Leucemia/genética , Leucemia/patologia , Mastocitose Sistêmica/classificação , Mutação , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Doenças Mieloproliferativas-Mielodisplásicas/classificação , Doenças Mieloproliferativas-Mielodisplásicas/diagnóstico , Doenças Mieloproliferativas-Mielodisplásicas/genética , Doenças Mieloproliferativas-Mielodisplásicas/patologia , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/patologia , Células-Tronco Neoplásicas/patologia , Pré-Leucemia/classificação , Terminologia como Assunto , Organização Mundial da SaúdeRESUMO
A 55 year-old man with hemolytic anemia is described. Careful clinical and laboratory studies showed that this condition was a manifestation of non-hereditary hemoglobinopathy N. The clinical symptoms suggested acquired hemoglobinopathy N that devloped parallel to myelodysplastic syndrome/myeloproliferative disease.
Assuntos
Hemoglobinopatias , Doenças Mieloproliferativas-Mielodisplásicas/complicações , Doenças Mieloproliferativas-Mielodisplásicas/diagnóstico , Talassemia alfa , Hemoglobinopatias/diagnóstico , Hemoglobinopatias/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Mieloproliferativas-Mielodisplásicas/classificação , Federação Russa , Síndrome , Talassemia alfa/diagnóstico , Talassemia alfa/etiologiaRESUMO
OBJECTIVES: Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are a group of rare and heterogeneous hematopoietic disorders that frequently present a diagnostic challenge. Here we present our institutional experience with next-generation sequencing (NGS), together with morphologic, flow cytometric, and cytogenetic evaluation, in the diagnosis of MDS/MPN, with particular emphasis on MDS/MPN unclassifiable (MPN-U). METHODS: We evaluated the morphologic, flow cytometric, cytogenetic, and molecular characteristics of all MDS/MPN cases that underwent NGS at our institution between April 2016 and February 2019. RESULTS: Thirty-seven cases of MDS/MPN were identified, including 14 cases of MDS/MPN-U. Ninety-seven percent harbored mutations and immunophenotypic aberrancies (36/37), while only 38% had cytogenetic abnormalities (12/32). The MDS/MPN-U group had the highest rate of myeloblast phenotypic abnormalities and had a high mutation rate of approximately 2.7 mutated genes per case, most commonly in JAK2, SRSF2, and ASXL1. CONCLUSIONS: No single ancillary study was abnormal in every case, but all cases had at least one abnormal finding, demonstrating the usefulness of a multiparameter approach to the diagnosis of MDS/MPN. Although a few specific mutations were found exclusively in MDS/MPN-U and JAK2 mutations were most prevalent, larger studies are needed to determine whether MDS/MPN-U has a mutational "fingerprint," which may aid in diagnosis and targeted therapy.
Assuntos
Doenças Mieloproliferativas-Mielodisplásicas/diagnóstico , Transtornos Mieloproliferativos/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Citogenética , Feminino , Citometria de Fluxo , Células Precursoras de Granulócitos/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Mutação , Taxa de Mutação , Doenças Mieloproliferativas-Mielodisplásicas/classificação , Doenças Mieloproliferativas-Mielodisplásicas/genética , Doenças Mieloproliferativas-Mielodisplásicas/patologia , Transtornos Mieloproliferativos/classificação , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/patologia , Análise de Sequência de DNA , Adulto JovemRESUMO
The clinicopathology of MDS and MPN are not mutually exclusive and for this reason the category of myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) exists. Several sub-entities have been included under the MDS/MPN umbrella, including MDS/MPN-unclassifiable (MDS/MPN-U) for those cases whose morphologic and clinical phenotype do not meet criteria to be classified as any other MDS/MPN sub-entity. Though potentially regarded as a wastebasket diagnosis, since its integration into myeloid disease classification, MDS/MPN-U has been refined with increasing understanding of the mutational and genomic events that drive particular clinicopathologic phenotypes, even within MDS/MPN-U. The prototypical example is the identification of SF3B1 mutations and its durable association with MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T), an entity previously buried within, but now a separate category outside of MDS/MPN-U. Continued and enhanced study of those entities under MDS/MPN-U, a perhaps provisional category itself, is likely to progressively identify commonality between many "unclassifiables" to establish a new classifiable diagnosis.
Assuntos
Síndromes Mielodisplásicas/classificação , Doenças Mieloproliferativas-Mielodisplásicas/classificação , Humanos , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/metabolismo , Síndromes Mielodisplásicas/terapia , Doenças Mieloproliferativas-Mielodisplásicas/genética , Doenças Mieloproliferativas-Mielodisplásicas/metabolismo , Doenças Mieloproliferativas-Mielodisplásicas/terapiaRESUMO
We report the case of a 68-year-old male with a diagnosis of unclassifiable myelodysplatic/myeloproliferative disease (WHO classification), under prolonged steroid treatment and unsuccesful chemotherapy response, who developed progressive asthenia, thoracic pain, minimal efforts dyspnea, and abdominal distension, that initially was suspicious of splenic rupture. Exploratory laparotomy showed multiple peritoneal implants, and a diagnosis of peritoneal tuberculosis was obtained from local biopsy. Definitive diagnosis included a positive result to culture and PCR urine test, together with a possible pleural and splenic tuberculous affectation. Response to tuberculostatic treatment was successful. To the best of our knowledge, this is the first reported case with such characteristics.
Assuntos
Doenças Mieloproliferativas-Mielodisplásicas/complicações , Peritonite Tuberculosa/etiologia , Idoso , Antituberculosos/uso terapêutico , Biópsia , Humanos , Masculino , Doenças Mieloproliferativas-Mielodisplásicas/classificação , Peritônio/patologia , Peritonite Tuberculosa/diagnóstico , Peritonite Tuberculosa/tratamento farmacológico , Peritonite Tuberculosa/patologia , Resultado do Tratamento , Organização Mundial da SaúdeRESUMO
Myelodysplastic and myeloproliferative neoplasms (MDS/MPN) is a rare and distinct group of myeloid neoplasms with overlapping MDS and MPN features. Next generation sequencing studies have led to an improved understanding of MDS/MPN disease biology by identifying recurrent somatic mutations. Combining the molecular findings to patho-morphologic features has improved the precision of diagnosis and prognostic models in MDS/MPN. We discuss and highlight these updates in MDS/MPN nomenclature and diagnostic criteria per revised 2016 WHO classification of myeloid neoplasms in this article. There is an ongoing effort for data integration allowing for comprehensive genomic characterization, development of improved prognostic tools, and investigation for novel therapies using an international front specific for MDS/MPN. In this article, we discuss updates in prognostic models and current state of treatment for MDS/MPN.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Modelos Biológicos , Doenças Mieloproliferativas-Mielodisplásicas/genética , Doenças Mieloproliferativas-Mielodisplásicas/mortalidade , Recidiva Local de Neoplasia/epidemiologia , Intervalo Livre de Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Incidência , Contagem de Leucócitos , Mutação , Doenças Mieloproliferativas-Mielodisplásicas/classificação , Doenças Mieloproliferativas-Mielodisplásicas/tratamento farmacológico , Prognóstico , Síndrome , Resultado do TratamentoAssuntos
Mastocitose Sistêmica/classificação , Medula Óssea/patologia , Progressão da Doença , Humanos , Leucemia de Mastócitos/classificação , Leucemia de Mastócitos/patologia , Mastocitose Sistêmica/genética , Mastocitose Sistêmica/patologia , Doenças Mieloproliferativas-Mielodisplásicas/classificação , Transtornos Mieloproliferativos/classificação , Transtornos Mieloproliferativos/patologia , Proteínas Proto-Oncogênicas c-kit/genética , Terminologia como Assunto , Organização Mundial da SaúdeRESUMO
Since the publication of the latest World Health Organization (WHO) classification in 2008, there has been a significant effort for clarification of unresolved questions, especially with the help of the rapidly developing field of molecular genetic studies, next-generation sequencing in particular. Numerous entities within the WHO categories of myeloproliferative neoplasms (MPNs) and myelodysplastic (MDS)/MPNs have been extensively studied, with large published series attempting to characterize and better define their morphologic and molecular genetic features. This emerging genetic landscape maintains a robust correlation with the various disease entities recognized by the WHO classification scheme based on a careful integration of detailed clinical information, bone marrow and peripheral blood morphology, immunohistology, and genomics. This brief review summarizes the current guidelines as they apply to diagnosing both the classical BCR-ABL1 negative MPN (polycythemia vera, essential thrombocythemia, and primary myelofibrosis) and the more common subtypes of MDS/MPN overlap syndromes. The more important recent molecular updates as well as the upcoming changes to the current WHO classification, expected to be published in late 2016, will also be briefly reviewed.
Assuntos
Doenças Mieloproliferativas-Mielodisplásicas/diagnóstico , Transtornos Mieloproliferativos/diagnóstico , Guias como Assunto , Humanos , Doenças Mieloproliferativas-Mielodisplásicas/classificação , Doenças Mieloproliferativas-Mielodisplásicas/genética , Transtornos Mieloproliferativos/classificação , Transtornos Mieloproliferativos/genética , Neoplasias/classificação , Neoplasias/genética , Organização Mundial da SaúdeAssuntos
Biomarcadores Tumorais/genética , Genômica/métodos , Mutação , Doenças Mieloproliferativas-Mielodisplásicas/classificação , Doenças Mieloproliferativas-Mielodisplásicas/genética , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Mieloproliferativas-Mielodisplásicas/patologia , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
According to the 2008 WHO classification, the category of myelodysplastic/myeloproliferative neoplasms (MDS/MPN) includes atypical chronic myeloid leukaemia (aCML), chronic myelomonocytic leukaemia (CMML), MDS/MPN-unclassifiable (MDS/MPN-U), juvenile myelomonocytic leukaemia (JMML) and a "provisional" entity, refractory anaemia with ring sideroblasts and thrombocytosis (RARS-T). The remarkable progress in our understanding of the somatic pathogenesis of MDS/MPN has made it clear that there is considerable overlap among these diseases at the molecular level, as well as layers of unexpected complexity. Deregulation of signalling plays an important role in many cases, and is clearly linked to more highly proliferative disease. Other mutations affect a range of other essential, interrelated cellular mechanisms, including epigenetic regulation, RNA splicing, transcription, and DNA damage response. The various combinations of mutations indicate a multi-step pathogenesis, which likely contributes to the marked clinical heterogeneity of these disorders. The delineation of complex clonal architectures may serve as the cornerstone for the identification of novel therapeutic targets and lead to better patient outcomes. This review summarizes some of the current knowledge of molecular pathogenetic lesions in the MDS/MPN subtypes that are seen in adults: atypical CML, CMML and MDS/MPN-U.