RESUMO
BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP), a common age-associated phenomenon, associates with increased risk of both hematological malignancy and cardiovascular disease. Although CHIP is known to increase the risk of myocardial infarction and heart failure, the influence of CHIP in cardiac arrhythmias, such as atrial fibrillation (AF), is less explored. METHODS: CHIP prevalence was determined in the UK Biobank, and incident AF analysis was stratified by CHIP status and clone size using Cox proportional hazard models. Lethally irradiated mice were transplanted with hematopoietic-specific loss of Tet2, hematopoietic-specific loss of Tet2 and Nlrp3, or wild-type control and fed a Western diet, compounded with or without NLRP3 (NLR [NACHT, LRR {leucine rich repeat}] family pyrin domain containing protein 3) inhibitor, NP3-361, for 6 to 9 weeks. Mice underwent in vivo invasive electrophysiology studies and ex vivo optical mapping. Cardiomyocytes from Ldlr-/- mice with hematopoietic-specific loss of Tet2 or wild-type control and fed a Western diet were isolated to evaluate calcium signaling dynamics and analysis. Cocultures of pluripotent stem cell-derived atrial cardiomyocytes were incubated with Tet2-deficient bone marrow-derived macrophages, wild-type control, or cytokines IL-1ß (interleukin 1ß) or IL-6 (interleukin 6). RESULTS: Analysis of the UK Biobank showed individuals with CHIP, in particular TET2 CHIP, have increased incident AF. Hematopoietic-specific inactivation of Tet2 increases AF propensity in atherogenic and nonatherogenic mouse models and is associated with increased Nlrp3 expression and CaMKII (Ca2+/calmodulin-dependent protein kinase II) activation, with AF susceptibility prevented by inactivation of Nlrp3. Cardiomyocytes isolated from Ldlr-/- mice with hematopoietic inactivation of Tet2 and fed a Western diet have impaired calcium release from the sarcoplasmic reticulum into the cytosol, contributing to atrial arrhythmogenesis. Abnormal sarcoplasmic reticulum calcium release was recapitulated in cocultures of cardiomyocytes with the addition of Tet2-deficient macrophages or cytokines IL-1ß or IL-6. CONCLUSIONS: We identified a modest association between CHIP, particularly TET2 CHIP, and incident AF in the UK Biobank population. In a mouse model of AF resulting from hematopoietic-specific inactivation of Tet2, we propose altered calcium handling as an arrhythmogenic mechanism, dependent on Nlrp3 inflammasome activation. Our data are in keeping with previous studies of CHIP in cardiovascular disease, and further studies into the therapeutic potential of NLRP3 inhibition for individuals with TET2 CHIP may be warranted.
Assuntos
Fibrilação Atrial , Hematopoiese Clonal , Proteínas de Ligação a DNA , Dioxigenases , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Proteínas Proto-Oncogênicas , Animais , Dioxigenases/metabolismo , Dioxigenases/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Fibrilação Atrial/metabolismo , Fibrilação Atrial/etiologia , Fibrilação Atrial/genética , Fibrilação Atrial/patologia , Inflamassomos/metabolismo , Humanos , Camundongos , Hematopoiese Clonal/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas/genética , Masculino , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Idoso , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Pessoa de Meia-Idade , Camundongos Knockout , Fatores de RiscoRESUMO
Germ line mutations in the RUNX1 gene cause familial platelet disorder (FPD), an inherited disease associated with lifetime risk to hematopoietic malignancies (HM). Patients with FPD frequently show clonal expansion of premalignant cells preceding HM onset. Despite the extensive studies on the role of RUNX1 in hematopoiesis, its function in the premalignant bone marrow (BM) is not well-understood. Here, we characterized the hematopoietic progenitor compartments using a mouse strain carrying an FPD-associated mutation, Runx1R188Q. Immunophenotypic analysis showed an increase in the number of hematopoietic stem and progenitor cells (HSPCs) in the Runx1R188Q/+ mice. However, the comparison of Sca-1 and CD86 markers suggested that Sca-1 expression may result from systemic inflammation. Cytokine profiling confirmed the dysregulation of interferon-response cytokines in the BM. Furthermore, the expression of CD48, another inflammation-response protein, was also increased in Runx1R188Q/+ HSPCs. The DNA-damage response activity of Runx1R188Q/+ hematopoietic progenitor cells was defective in vitro, suggesting that Runx1R188Q may promote genomic instability. The differentiation of long-term repopulating HSCs was reduced in Runx1R188Q/+ recipient mice. Furthermore, we found that Runx1R188Q/+ HSPCs outcompete their wild-type counterparts in bidirectional repopulation assays, and that the genetic makeup of recipient mice did not significantly affect the clonal dynamics under this setting. Finally, we demonstrate that Runx1R188Q predisposes to HM in cooperation with somatic mutations found in FPDHM, using 3 mouse models. These studies establish a novel murine FPDHM model and demonstrate that germ line Runx1 mutations induce a premalignant phenotype marked by BM inflammation, selective expansion capacity, defective DNA-damage response, and predisposition to HM.
Assuntos
Transtornos Plaquetários , Neoplasias Hematológicas , Animais , Camundongos , Humanos , Mutação em Linhagem Germinativa , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Suscetibilidade a Doenças , Transtornos Plaquetários/genética , Inflamação/genética , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/complicações , DNARESUMO
Background: Clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance (CCUS) are defined by somatic mutations in genes associated with myeloid neoplasms (MN) at a variant allele fraction (VAF) ≥ 0.02, in the absence and presence of cytopenia, respectively. CHIP/CCUS is highly prevalent in adults and defining predictors of MN risk would aid clinical management and research. Methods: We analyzed sequenced exomes of healthy UK Biobank (UKB) participants (n = 438,890) in separate derivation and validation cohorts. Genetic mutations, laboratory values, and MN outcomes were used in conditional probability-based recursive partitioning and Cox regression to determine predictors of incident MN. Combined statistical weights defined a clonal hematopoiesis risk score (CHRS). Independent CHIP/CCUS patient cohorts were used to test prognostic capability of the CHRS in the clinical setting. Results: Recursive partitioning distinguished CHIP/CCUS cases with 10-year probabilities of MN ranging from 0.0078 - 0.85. Multivariable analysis validated partitioning variables as predictors of MN. Key features, including single DNMT3A mutations, high risk mutations, ≥ 2 mutations, VAF ≥ 0.2, age ≥ 65 years, CCUS vs CHIP and red blood cell indices, influenced MN risk in variable direction. The CHRS defined low risk (n = 10018, 88.4%), intermediate risk (n = 1196, 10.5%), and high risk (n = 123, 1.1%) groups. In clinical cohorts, most MN events occurred in high risk CHIP/CCUS patients. Conclusions: The CHRS provides simple prognostic framework for CHIP/CCUS, distinguishing a high risk minority from the majority of CHIP/CCUS which has minimal risk for progression to MN.
RESUMO
Chronic liver disease is a major public health burden worldwide1. Although different aetiologies and mechanisms of liver injury exist, progression of chronic liver disease follows a common pathway of liver inflammation, injury and fibrosis2. Here we examined the association between clonal haematopoiesis of indeterminate potential (CHIP) and chronic liver disease in 214,563 individuals from 4 independent cohorts with whole-exome sequencing data (Framingham Heart Study, Atherosclerosis Risk in Communities Study, UK Biobank and Mass General Brigham Biobank). CHIP was associated with an increased risk of prevalent and incident chronic liver disease (odds ratio = 2.01, 95% confidence interval (95% CI) [1.46, 2.79]; P < 0.001). Individuals with CHIP were more likely to demonstrate liver inflammation and fibrosis detectable by magnetic resonance imaging compared to those without CHIP (odds ratio = 1.74, 95% CI [1.16, 2.60]; P = 0.007). To assess potential causality, Mendelian randomization analyses showed that genetic predisposition to CHIP was associated with a greater risk of chronic liver disease (odds ratio = 2.37, 95% CI [1.57, 3.6]; P < 0.001). In a dietary model of non-alcoholic steatohepatitis, mice transplanted with Tet2-deficient haematopoietic cells demonstrated more severe liver inflammation and fibrosis. These effects were mediated by the NLRP3 inflammasome and increased levels of expression of downstream inflammatory cytokines in Tet2-deficient macrophages. In summary, clonal haematopoiesis is associated with an elevated risk of liver inflammation and chronic liver disease progression through an aberrant inflammatory response.
Assuntos
Hematopoiese Clonal , Suscetibilidade a Doenças , Hepatite , Cirrose Hepática , Animais , Camundongos , Hematopoiese Clonal/genética , Hepatite/genética , Inflamação/genética , Cirrose Hepática/genética , Hepatopatia Gordurosa não Alcoólica/genética , Razão de Chances , Progressão da DoençaRESUMO
Age-related diseases are frequently linked to pathological immune dysfunction, including excessive inflammation, autoreactivity and immunodeficiency. Recent analyses of human genetic data have revealed that somatic mutations and mosaic chromosomal alterations in blood cells - a condition known as clonal haematopoiesis (CH) - are associated with ageing and pathological immune dysfunction. Indeed, large-scale epidemiological studies and experimental mouse models have demonstrated that CH can promote cardiovascular disease, chronic obstructive pulmonary disease, chronic liver disease, osteoporosis and gout. The genes most frequently mutated in CH, the epigenetic regulators TET2 and DNMT3A, implicate increased chemokine expression and inflammasome hyperactivation in myeloid cells as a possible mechanistic connection between CH and age-related diseases. In addition, TET2 and DNMT3A mutations in lymphoid cells have been shown to drive methylation-dependent alterations in differentiation and function. Here we review the observational and mechanistic studies describing the connection between CH and pathological immune dysfunction, the effects of CH-associated genetic alterations on the function of myeloid and lymphoid cells, and the clinical and therapeutic implications of CH as a target for immunomodulation.
Assuntos
DNA (Citosina-5-)-Metiltransferases , DNA Metiltransferase 3A , Humanos , Camundongos , Animais , DNA (Citosina-5-)-Metiltransferases/genética , Hematopoiese Clonal , Hematopoese/genética , Mutação , Sistema ImunitárioRESUMO
Myelofibrosis is a progressive bone marrow malignancy associated with monocytosis, and is believed to promote the pathological remodelling of the extracellular matrix. Here we show that the mechanical properties of myelofibrosis, namely the liquid-to-solid properties (viscoelasticity) of the bone marrow, contribute to aberrant differentiation of monocytes. Human monocytes cultured in stiff, elastic hydrogels show proinflammatory polarization and differentiation towards dendritic cells, as opposed to those cultured in a viscoelastic matrix. This mechanically induced cell differentiation is blocked by inhibiting a myeloid-specific isoform of phosphoinositide 3-kinase, PI3K-γ. We further show that murine bone marrow with myelofibrosis has a significantly increased stiffness and unveil a positive correlation between myelofibrosis grading and viscoelasticity. Treatment with a PI3K-γ inhibitor in vivo reduced frequencies of monocyte and dendritic cell populations in murine bone marrow with myelofibrosis. Moreover, transcriptional changes driven by viscoelasticity are consistent with transcriptional profiles of myeloid cells in other human fibrotic diseases. These results demonstrate that a fibrotic bone marrow niche can physically promote a proinflammatory microenvironment.
Assuntos
Mielofibrose Primária , Animais , Medula Óssea/patologia , Diferenciação Celular , Fibrose , Humanos , Camundongos , Monócitos , Fosfatidilinositol 3-Quinases , Mielofibrose Primária/patologiaRESUMO
Gout is a common inflammatory arthritis caused by precipitation of monosodium urate (MSU) crystals in individuals with hyperuricemia. Acute flares are accompanied by secretion of proinflammatory cytokines, including interleukin-1ß (IL-1ß). Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition predisposing to hematologic cancers and cardiovascular disease. CHIP is associated with elevated IL-1ß, thus we investigated CHIP as a risk factor for gout. To test the clinical association between CHIP and gout, we analyzed whole exome sequencing data from 177 824 individuals in the MGB Biobank (MGBB) and UK Biobank (UKB). In both cohorts, the frequency of gout was higher among individuals with CHIP than without CHIP (MGBB, CHIP with variant allele fraction [VAF] ≥2%: odds ratio [OR], 1.69; 95% CI, 1.09-2.61; P = .0189; UKB, CHIP with VAF ≥10%: OR, 1.25; 95% CI, 1.05-1.50; P = .0133). Moreover, individuals with CHIP and a VAF ≥10% had an increased risk of incident gout (UKB: hazard ratio [HR], 1.28; 95% CI, 1.06-1.55; P = .0107). In murine models of gout pathogenesis, animals with Tet2 knockout hematopoietic cells had exaggerated IL-1ß secretion and paw edema upon administration of MSU crystals. Tet2 knockout macrophages elaborated higher levels of IL-1ß in response to MSU crystals in vitro, which was ameliorated through genetic and pharmacologic Nlrp3 inflammasome inhibition. These studies show that TET2-mutant CHIP is associated with an increased risk of gout in humans and that MSU crystals lead to elevated IL-1ß levels in Tet2 knockout murine models. We identify CHIP as an amplifier of NLRP3-dependent inflammatory responses to MSU crystals in patients with gout.
Assuntos
Dioxigenases , Gota , Animais , Hematopoiese Clonal , Proteínas de Ligação a DNA/genética , Dioxigenases/genética , Gota/genética , Humanos , Inflamassomos/genética , Interleucina-1beta/genética , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Ácido Úrico/química , Ácido Úrico/farmacologiaRESUMO
Osteoporosis is caused by an imbalance of osteoclasts and osteoblasts, occurring in close proximity to hematopoietic cells in the bone marrow. Recurrent somatic mutations that lead to an expanded population of mutant blood cells is termed clonal hematopoiesis of indeterminate potential (CHIP). Analyzing exome sequencing data from the UK Biobank, we found CHIP to be associated with increased incident osteoporosis diagnoses and decreased bone mineral density. In murine models, hematopoietic-specific mutations in Dnmt3a, the most commonly mutated gene in CHIP, decreased bone mass via increased osteoclastogenesis. Dnmt3a-/- demethylation opened chromatin and altered activity of inflammatory transcription factors. Bone loss was driven by proinflammatory cytokines, including Irf3-NF-κB-mediated IL-20 expression from Dnmt3a mutant macrophages. Increased osteoclastogenesis due to the Dnmt3a mutations was ameliorated by alendronate or IL-20 neutralization. These results demonstrate a novel source of osteoporosis-inducing inflammation.
Assuntos
Hematopoiese Clonal/genética , DNA Metiltransferase 3A/genética , Osteoporose/genética , Adulto , Idoso , Alendronato/farmacologia , Animais , Anticorpos Neutralizantes/farmacologia , Diferenciação Celular/genética , Hematopoiese Clonal/fisiologia , DNA Metiltransferase 3A/metabolismo , Feminino , Humanos , Interleucinas/imunologia , Interleucinas/metabolismo , Masculino , Camundongos Knockout , Pessoa de Meia-Idade , Osteoclastos/patologia , Osteoporose/sangue , Osteoporose/tratamento farmacológico , Osteoporose/fisiopatologiaRESUMO
Clonal hematopoiesis (CH) results from somatic genomic alterations that drive clonal expansion of blood cells. Somatic gene mutations associated with hematologic malignancies detected in hematopoietic cells of healthy individuals, referred to as CH of indeterminate potential (CHIP), have been associated with myeloid malignancies, while mosaic chromosomal alterations (mCAs) have been associated with lymphoid malignancies. Here, we analyzed CHIP in 55,383 individuals and autosomal mCAs in 420,969 individuals with no history of hematologic malignancies in the UK Biobank and Mass General Brigham Biobank. We distinguished myeloid and lymphoid somatic gene mutations, as well as myeloid and lymphoid mCAs, and found both to be associated with risk of lineage-specific hematologic malignancies. Further, we performed an integrated analysis of somatic alterations with peripheral blood count parameters to stratify the risk of incident myeloid and lymphoid malignancies. These genetic alterations can be readily detected in clinical sequencing panels and used with blood count parameters to identify individuals at high risk of developing hematologic malignancies.
Assuntos
Hematopoiese Clonal/genética , Hematopoiese Clonal/fisiologia , Neoplasias Hematológicas/patologia , Células-Tronco Hematopoéticas/citologia , Contagem de Células Sanguíneas , Aberrações Cromossômicas , Neoplasias Hematológicas/genética , HumanosRESUMO
Clonal hematopoiesis results from somatic mutations in cancer driver genes in hematopoietic stem cells. We sought to identify novel drivers of clonal expansion using an unbiased analysis of sequencing data from 84,683 persons and identified common mutations in the 5-methylcytosine reader, ZBTB33, as well as in YLPM1, SRCAP, and ZNF318. We also identified these mutations at low frequency in myelodysplastic syndrome patients. Zbtb33 edited mouse hematopoietic stem and progenitor cells exhibited a competitive advantage in vivo and increased genome-wide intron retention. ZBTB33 mutations potentially link DNA methylation and RNA splicing, the two most commonly mutated pathways in clonal hematopoiesis and MDS.
Assuntos
Hematopoiese Clonal , Síndromes Mielodisplásicas , Animais , Hematopoese/genética , Células-Tronco Hematopoéticas , Humanos , Camundongos , Síndromes Mielodisplásicas/genética , Splicing de RNA/genética , Fatores de Transcrição/genéticaRESUMO
TP53, which encodes the tumor suppressor p53, is the most frequently mutated gene in human cancer. The selective pressures shaping its mutational spectrum, dominated by missense mutations, are enigmatic, and neomorphic gain-of-function (GOF) activities have been implicated. We used CRISPR-Cas9 to generate isogenic human leukemia cell lines of the most common TP53 missense mutations. Functional, DNA-binding, and transcriptional analyses revealed loss of function but no GOF effects. Comprehensive mutational scanning of p53 single-amino acid variants demonstrated that missense variants in the DNA-binding domain exert a dominant-negative effect (DNE). In mice, the DNE of p53 missense variants confers a selective advantage to hematopoietic cells on DNA damage. Analysis of clinical outcomes in patients with acute myeloid leukemia showed no evidence of GOF for TP53 missense mutations. Thus, a DNE is the primary unit of selection for TP53 missense mutations in myeloid malignancies.
Assuntos
Leucemia Mieloide Aguda/genética , Mutação de Sentido Incorreto , Seleção Genética , Proteína Supressora de Tumor p53/genética , Animais , Sistemas CRISPR-Cas , Mutação com Ganho de Função , Genes Dominantes , Humanos , Células K562 , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
NPM1-mutated myeloid neoplasms (NPM1 + MNs) with <20% blood or bone marrow blasts are rare and have been previously shown in limited case series to exhibit an aggressive clinical course. We assembled the largest cohort of NPM1 + MN cases to date (n = 45) and compared it with NPM1 - MN (n = 95) and NPM1 + de novo acute myeloid leukemia (AML; n = 119) patients. Compared with NPM1 - MN, NPM1 + MN were associated with younger age (P = .007), a normal karyotype (P < .0001), more frequent mutations involving DNMT3A (P = .01) and PTPN11 (P = .03), and fewer involving ASXL1 (P = .003), RUNX1 (P = .0004), and TP53 (P = .02). Mutations involving IDH1 or IDH2 (IDH1/2) (P = .007) and FLT3 (internal tandem duplication, P < .0001; noninternal tandem duplication, P = .01) were less frequent in NPM1 + MN than in NPM1 + AML. In multivariable analyses performed in patients with myelodysplastic syndrome only, total mutation count (hazard ratio [HR], 1.3; P = .05), NPM1 mutation (HR, 3.6; P = .02), TP53 mutation (HR, 5.2; P = .01), and higher International Prognostic Scoring System-R score (HR, 1.7; P = .0003) were independently associated with shorter overall survival, whereas stem cell transplant conferred a favorable effect (HR, 0.1; P < .0001). These data suggest that NPM1 + MN are biologically distinct from NPM1 - MN. Similar to NPM1 + AML, patients with NPM1-mutated myelodysplastic syndrome may benefit from more intensive therapeutic regimens.
Assuntos
Síndromes Mielodisplásicas/patologia , Proteínas Nucleares/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , DNA (Citosina-5-)-Metiltransferases/genética , DNA Metiltransferase 3A , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/mortalidade , Nucleofosmina , Prognóstico , Modelos de Riscos Proporcionais , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Taxa de Sobrevida , Proteína Supressora de Tumor p53/genéticaRESUMO
Elevated peripheral blood (PB) cell counts, such as leukocytosis, thrombocytosis, and polycythemia, are often the presenting symptom in patients with myeloproliferative neoplasms (MPN). Because cythemias are nonspecific and may reflect either a reactive or neoplastic process, diagnostic workup of these patients is complicated and requires integration of numerous diagnostic modalities. Careful morphologic evaluation of the PB smear may provide insights into the underlying cause of the abnormal counts (such as the presence of teardrop erythrocytes in myelofibrosis or granulocytic dysplasia with left shift in atypical chronic myeloid leukemia). However, these morphologic findings need to be interpreted in concert with clinical findings and other laboratory results. In recent years, there has been a wealth of new genetic data in the field of MPN and many recurrent mutations have been identified, especially in cases lacking Philadelphia chromosome. Many of these genes impact the diagnosis and/or prognosis. Although certain mutations are preferentially enriched in specific MPN types, none of these mutations are disease defining; therefore, a thorough workup should always include a bone marrow biopsy for morphologic evaluation and diagnosis. This review will describe a comprehensive approach to the diagnosis of various MPN, with an emphasis on the diagnostic and prognostic implications of recurrent mutations in MPN.
Assuntos
Neoplasias Hematológicas , Mutação , Transtornos Mieloproliferativos , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , Humanos , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/genética , PrognósticoRESUMO
The Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) share similar molecular characteristics in that they frequently harbor hotspot mutations in JAK2, CALR or MPL, leading to activated JAK/STAT signaling. However, these MPN have distinct symptoms, morphology, and natural histories, including different tendencies to progress to fibrosis. Although the role of inflammation in tissue fibrosis is well recognized, inflammatory gene expression in bone marrows involved by MPN has been understudied. We analyzed the expression of inflammatory genes by directly measuring RNA transcript abundance in bone marrow biopsies of 108 MPN patients. Unsupervised analyses identified gene expression patterns that distinguish prefibrotic (grade 1-2) MPN from overtly fibrotic (grade 2-3) MPN with high sensitivity and specificity in two independent cohorts. Furthermore, prefibrotic and overtly fibrotic MPN are separable into subsets with different activities in biological pathways linked to inflammation, including cytokines, chemokines, interferon response, and toll-like receptor signaling. In conclusion, this study demonstrates that MPN with overt fibrosis is associated with significant inflammatory gene upregulation in the bone marrow, revealing potential roles for multiple pro-inflammatory signaling networks in the development of myelofibrosis and suggesting potential therapeutic mechanisms to alleviate this process in the bone marrow microenvironment.
Assuntos
Medula Óssea/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Neoplasias Hematológicas/metabolismo , Mielofibrose Primária/metabolismo , Idoso , Medula Óssea/patologia , Feminino , Fibrose , Neoplasias Hematológicas/patologia , Humanos , Inflamação/metabolismo , Inflamação/patologia , Masculino , Análise em Microsséries , Pessoa de Meia-Idade , Mielofibrose Primária/patologiaRESUMO
The introduction of next-generation sequencing has broadened the genetic landscape of myeloproliferative neoplasms (MPNs) beyond JAK2, MPL, and CALR. However, the biological role and clinical impact of most other mutations are not well defined. We interrogated 101 genes in 143 BCR-ABL1-negative MPNs in chronic phase from 2 large institutions. We detected SF3B1 mutations in 15 cases (10%) and set to investigate the clinical, morphologic, and molecular features of SF3B1 mutated (SF3B1+) MPNs in comparison to SF3B1 wild-type (SF3B1-) cases and to identify distinctive features with myelodysplastic/myeloproliferative neoplasms with ring sideroblasts (RS) and thrombocytosis, which can show partial clinical and morphological overlap with MPNs. SF3B1+ cases were enriched in primary myelofibrosis in both prefibrotic and fibrotic stage, but mutations of SF3B1 seem to occur only as a late event in the fibrotic phase of essential thrombocythemia and polycythemia vera. SF3B1+ MPNs showed borderline lower hemoglobin but no other clinical or molecular differences compared to SF3B1- MPNs. Of note, RS were present only in a subset of SF3B1+ cases (4/10) without any other feature of erythroid or granulocytic dysplasia. Our results suggest that mutations in SF3B1 are not a rare event in MPNs, especially in primary myelofibrosis and during late fibrotic stages of essential thrombocythemia and polycythemia vera, but are not associated with myelodysplastic progression. Careful examination of bone marrow and peripheral blood for morphologic dysplasia is crucial to reach the correct diagnosis and avoid a misdiagnosis of myelodysplastic/myeloproliferative neoplasms with RS and thrombocytosis, a pitfall with potential prognostic and therapeutic implications.