RESUMEN
Germ line DDX41 variants have been implicated in late-onset myeloid neoplasms (MNs). Despite an increasing number of publications, many important features of DDX41-mutated MNs remain to be elucidated. Here we performed a comprehensive characterization of DDX41-mutated MNs, enrolling a total of 346 patients with DDX41 pathogenic/likely-pathogenic (P/LP) germ line variants and/or somatic mutations from 9082 MN patients, together with 525 first-degree relatives of DDX41-mutated and wild-type (WT) patients. P/LP DDX41 germ line variants explained â¼80% of known germ line predisposition to MNs in adults. These risk variants were 10-fold more enriched in Japanese MN cases (n = 4461) compared with the general population of Japan (n = 20 238). This enrichment of DDX41 risk alleles was much more prominent in male than female (20.7 vs 5.0). P/LP DDX41 variants conferred a large risk of developing MNs, which was negligible until 40 years of age but rapidly increased to 49% by 90 years of age. Patients with myelodysplastic syndromes (MDS) along with a DDX41-mutation rapidly progressed to acute myeloid leukemia (AML), which was however, confined to those having truncating variants. Comutation patterns at diagnosis and at progression to AML were substantially different between DDX41-mutated and WT cases, in which none of the comutations affected clinical outcomes. Even TP53 mutations made no exceptions and their dismal effect, including multihit allelic status, on survival was almost completely mitigated by the presence of DDX41 mutations. Finally, outcomes were not affected by the conventional risk stratifications including the revised/molecular International Prognostic Scoring System. Our findings establish that MDS with DDX41-mutation defines a unique subtype of MNs that is distinct from other MNs.
Asunto(s)
ARN Helicasas DEAD-box , Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Trastornos Mieloproliferativos , Adulto , Anciano de 80 o más Años , Femenino , Humanos , Masculino , ARN Helicasas DEAD-box/genética , Células Germinativas , Leucemia Mieloide Aguda/genética , Mutación , Síndromes Mielodisplásicos/genética , Trastornos Mieloproliferativos/genéticaRESUMEN
Acute erythroid leukemia (AEL) is a unique subtype of acute myeloid leukemia characterized by erythroid predominance and dysplasia. It is classified into two subtypes: pure erythroid (PEL) and erythroid/myeloid (EML) phenotypes. To understand the mechanism of the erythroid dominant phenotype of AEL and identify potential therapeutic targets for AEL, we analyzed 105 AEL and 214 non-AEL cases using whole-genome/exome and/or targeted-capture sequencing, with SNP probes for detecting copy number abnormalities. We also performed a transcriptome analysis of 12 AEL samples. Combining publicly available sequencing data, AEL was genetically clustered into four groups according to mutational status in TP53, STAG2, and NPM1 genes. Conspicuously, highly recurrent gains and amplifications affecting EPOR, JAK2, and/or ERG/ETS2 were recurrently detected in AEL cases, almost exclusively found in TP53-mutated cases. Among these, gains/amplifications of EPOR/JAK2 were more highly enriched in PEL than EML cases. Along with the activated STAT5 pathway, a common feature across all AEL cases, these AEL cases exhibited enhanced cell proliferation and heme metabolism, and they showed high sensitivity to ruxolitinib in in vitro and in xenograft models, highlighting the potential role of JAK2 inhibition in AEL therapeutics.
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Leucemia Eritroblástica Aguda , Leucemia Mieloide Aguda , Niño , Exoma , Humanos , Leucemia Eritroblástica Aguda/diagnóstico , Leucemia Eritroblástica Aguda/tratamiento farmacológico , Leucemia Eritroblástica Aguda/genética , Leucemia Mieloide Aguda/genética , Mutación , FenotipoRESUMEN
Cord blood transplantation (CBT) is an effective therapeutic option for adults with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) after the conventional cyclophosphamide and total body irradiation (CY/TBI) regimen, but posttransplant relapse is still of high importance. High-dose cytarabine (HDCA) can be added to CY/TBI for an intensified regimen; however, its additional effects have not yet been completely elucidated. Therefore, we conducted a cohort study to compare the prognosis of HDCA/CY/TBI (n = 617) and CY/TBI (n = 312) in CBT for AML/MDS, using a Japanese transplant registry database. The median age was 40 years, and 86.2% of the patients had AML; high-risk disease was observed in 56.2% of the patients. The median follow-up period after CBT was approximately 3.5 years. Overall survival was significantly superior in the HDCA/CY/TBI group (adjusted hazard ratio [HR], 0.56; 95% confidence interval [CI], 0.45-0.69; P < .01), and tumor-related mortality was lower (HR, 0.50; P < .01). The incidence of grade II to IV acute graft-vs-host disease (aGVHD) and chronic GVHD was significantly higher in the HDCA/CY/TBI group (HR, 1.33 and 2.30, respectively), but not grade III to IV aGVHD. Incidence of infectious episodes showed no significant difference. Nonrelapse mortality was not increased by the addition of HDCA. Higher-dose CA (12 rather than 8 g/m(2)) was more effective, particularly in patients at high-risk for disease. This study is the first to show the superiority of HDCA/CY/TBI to CY/TBI in CBT for AML/MDS. A large-scale prospective study is warranted to establish new conditioning regimens including HDCA administration.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Células Madre de Sangre del Cordón Umbilical , Leucemia Mieloide/terapia , Síndromes Mielodisplásicos/terapia , Recurrencia Local de Neoplasia/terapia , Irradiación Corporal Total , Adolescente , Adulto , Anciano , Estudios de Cohortes , Terapia Combinada , Ciclofosfamida/administración & dosificación , Citarabina/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mieloide/mortalidad , Leucemia Mieloide/patología , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/mortalidad , Síndromes Mielodisplásicos/patología , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Pronóstico , Tasa de Supervivencia , Acondicionamiento Pretrasplante , Trasplante Homólogo , Adulto JovenRESUMEN
Common variable immunodeficiency (CVID) is a primary B cell immunodeficiency disorder. Symptoms do not develop immediately after birth, and patients are often diagnosed in childhood and adulthood. These patients often develop autoimmune diseases and malignant tumors. We herein report a 50-year-old woman with severe hypogammaglobulinemia and recurrent respiratory tract infections who was diagnosed with CVID. Target sequencing showed a TNFRSF13B heterozygous frameshift variant. The patient had many comorbidities, probably caused by a CVID-induced immune imbalance. Physicians who treat adult patients are often unaware of CVID. CVID should be recognized as a differential diagnosis in hypogammaglobulinemia and recurrent infections.
RESUMEN
Allogenic hematopoietic stem cell transplantation (allo-HSCT) is not a standard therapy for solid cancer because of its high toxicity and insufficient evidence levels. However, the potential graft-versus-solid-tumor (GVT) effect of this therapy has been discussed. Many case reports have also described treatment effects of allo-HSCT in patients with hematologic malignancies and active solid tumors. A 38-year-old woman treated with fulvestrant and abemaciclib for recurrent breast cancer with multiple lung metastases was diagnosed with myelodysplastic syndrome (MDS) with increased blasts 2. She was classified as adverse risk by the 2017 European LeukemiaNet risk stratification and as very high risk by the Molecular International Prognostic Scoring System. Breast cancer treatment was interrupted and venetoclax and azacitidine therapy was started. Complete hematologic response was achieved after three cycles. However, multiple lung metastases from the breast cancer remained. The patient then underwent umbilical cord blood transplantation. She has maintained complete remission of MDS as of 1 year post-transplantation, without serious complications. Lung metastatic activity on FDG-PET/CT scan also completely disappeared by half a year post-transplantation, and this response has continued as of 1 year post-transplantation. This favorable treatment course suggests the existence of a GVT effect.
Asunto(s)
Neoplasias de la Mama , Trasplante de Células Madre de Sangre del Cordón Umbilical , Neoplasias Pulmonares , Síndromes Mielodisplásicos , Humanos , Femenino , Síndromes Mielodisplásicos/terapia , Neoplasias Pulmonares/secundario , Adulto , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Inducción de Remisión , Resultado del TratamientoAsunto(s)
Sarcoma de Células Dendríticas Foliculares/genética , Infecciones por VIH/genética , Linfoma de Células B Grandes Difuso/genética , Neoplasias Primarias Secundarias/genética , Proteínas Proto-Oncogénicas c-myc/genética , Translocación Genética , Sarcoma de Células Dendríticas Foliculares/metabolismo , Sarcoma de Células Dendríticas Foliculares/patología , Infecciones por VIH/metabolismo , Infecciones por VIH/patología , Humanos , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/patología , Masculino , Persona de Mediana Edad , Neoplasias Primarias Secundarias/metabolismo , Neoplasias Primarias Secundarias/patología , Proteínas Proto-Oncogénicas c-myc/metabolismoRESUMEN
SETBP1 is a potential epigenetic regulator whose hotspot mutations preventing proteasomal degradation are recurrently detected in myeloid malignancies with poor prognosis. It is believed that the mutant SETBP1 exerts amplified effects of wild-type SETBP1 rather than neomorphic functions. This indicates that dysregulated quantitative control of SETBP1 would result in the transformation of hematopoietic cells. However, little is known about the roles of endogenous SETBP1 in malignant and normal hematopoiesis. Thus, we integrated the analyses of primary AML and healthy samples, cancer cell lines, and a newly generated murine model, Vav1-iCre;Setbp1fl/fl. Despite the expression in long-term hematopoietic stem cells, SETBP1 depletion in normal hematopoiesis minimally alters self-renewal, differentiation, or reconstitution in vivo. Indeed, its loss does not profoundly alter transcription or chromatin accessibilities. Furthermore, although AML with high SETBP1 mRNA is associated with genetic and clinical characteristics for dismal outcomes, SETBP1 is dispensable for the development or maintenance of AML. Contrary to the evidence that SETBP1 mutations are restricted to myeloid malignancies, dependency on SETBP1 mRNA expression is not observed in AML. These unexpected results shed light on the unrecognized idea that a physiologically nonessential gene can act as an oncogene when the machinery of protein degradation is damaged.
Asunto(s)
Hematopoyesis , Leucemia Mieloide Aguda , Animales , Humanos , Ratones , Proteínas Portadoras/genética , Diferenciación Celular , Hematopoyesis/genética , Células Madre Hematopoyéticas/metabolismo , Leucemia Mieloide Aguda/patología , Mutación , Proteínas Nucleares/genéticaRESUMEN
Azacitidine is a mainstay of therapy for myelodysplastic syndrome (MDS)-related diseases. The purpose of our study is to elucidate the effect of gene mutations on hematological response and overall survival (OS), particularly focusing on their posttreatment clone size. We enrolled a total of 449 patients with MDS or related myeloid neoplasms. They were analyzed for gene mutations in pretreatment (n = 449) and posttreatment (n = 289) bone marrow samples using targeted-capture sequencing to assess the impact of gene mutations and their posttreatment clone size on treatment outcomes. In Cox proportional hazard modeling, multihit TP53 mutation (hazard ratio [HR], 2.03; 95% confidence interval [CI], 1.42-2.91; P < .001), EZH2 mutation (HR, 1.71; 95% CI, 1.14-2.54; P = .009), and DDX41 mutation (HR, 0.33; 95% CI, 0.17-0.62; P < .001), together with age, high-risk karyotypes, low platelets, and high blast counts, independently predicted OS. Posttreatment clone size accounting for all drivers significantly correlated with International Working Group (IWG) response (P < .001, using trend test), except for that of DDX41-mutated clones, which did not predict IWG response. Combined, IWG response and posttreatment clone size further improved the prediction of the original model and even that of a recently proposed molecular prediction model, the molecular International Prognostic Scoring System (IPSS-M; c-index, 0.653 vs 0.688; P < .001, using likelihood ratio test). In conclusion, evaluation of posttreatment clone size, together with the pretreatment mutational profile as well as the IWG response play a role in better prognostication of azacitidine-treated patients with myelodysplasia.
Asunto(s)
Síndromes Mielodisplásicos , Trastornos Mieloproliferativos , Neoplasias , Humanos , Pronóstico , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/genética , Resultado del Tratamiento , AzacitidinaRESUMEN
Although about 10 to 15% of patients with multiple myeloma (MM) develop AL amyloidosis, liver-restricted fatal amyloidosis is rare. We encountered such an MM patient. A 73-year-old female without a history of carpal tunnel syndrome was diagnosed with IgG-κ MM (Stage I by Durie & Salmon) in January, 2005. Because MM was exacerbated to Stage III in May, 2007, VAD (vincristine, adriamycin, dexamethasone) chemotherapy was performed with minor response, despite 3 courses of this regimen. Three courses of salvage chemotherapy (cyclophosphamide+melphalan; CM) were then performed with near partial response. In March, 2008, just before the 4th cycle of CM chemotherapy, she was slightly icteric with elevated biliary tract enzymes; therefore, treatment was switched to oral cyclophosphamide and prednisolone. At this time, she did not have macroglossia, skin eruption, gastrointestinal dysfunction, or bleeding. Echocardiography was also non-specific. One month later, she developed a marked bleeding tendency and leg edema. Laboratory tests showed a severe deterioration in liver function. In the middle of May, 2008, she progressed to hepatic coma and died of intracranial hemorrhage several days later. Autopsy showed that the liver was almost substituted by AL amyloid substance.
Asunto(s)
Amiloidosis/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Fallo Hepático/etiología , Mieloma Múltiple/tratamiento farmacológico , Anciano , Amiloidosis/complicaciones , Amiloidosis/diagnóstico , Dexametasona/uso terapéutico , Resultado Fatal , Femenino , Hemorragia/complicaciones , Humanos , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas , Melfalán/uso terapéutico , Mieloma Múltiple/complicaciones , Mieloma Múltiple/diagnóstico , Vincristina/uso terapéuticoRESUMEN
Werner syndrome (WS) is a progeroid syndrome caused by mutations in the WRN gene, which encodes the RecQ type DNA helicase for the unwinding of unusual DNA structures and is implicated in DNA replication, DNA repair, and telomere maintenance. patients with WS are prone to develop malignant neoplasms, including hematological malignancies. However, the pathogenesis of WS-associated hematological malignancies remains uncharacterized. Here we investigated the somatic gene mutations in WS-associated myelodysplastic syndrome/acute myeloid leukemia (MDS/AML). Whole-exome sequencing (WES) of 4 patients with WS with MDS/AML revealed that all patients had somatic mutations in TP53 but no other recurrent mutations in MDS/AML. TP53 mutations were identified at low allele frequencies at more than one year before the MDS/AML stage. All 4 patients had complex chromosomal abnormalities including those that involved TP53. Targeted sequencing of nine patients with WS without apparent blood abnormalities did not detect recurrent mutations in MDS/AML except for a PPM1D mutation. These results suggest that patients with WS are apt to acquire TP53 mutations and/or chromosomal abnormalities involving TP53, rather than other MDS/AML-related mutations. TP53 mutations are frequently associated with prior exposure to chemotherapy; however, all four patients with WS with TP53 mutations/deletions had not received any prior chemotherapy, suggesting a pathogenic link between WRN mutations and p53 insufficiency. These results indicate that WS hematopoietic stem cells with WRN insufficiency acquire competitive fitness by inactivating p53, which may cause complex chromosomal abnormalities and the subsequent development of myeloid malignancies. These findings promote our understanding of the pathogenesis of myeloid malignancies associated with progeria.
Asunto(s)
Neoplasias Hematológicas , Leucemia Mieloide Aguda , Trastornos Mieloproliferativos , Progeria , Síndrome de Werner , Aberraciones Cromosómicas , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Mutación , Prevalencia , Progeria/genética , Proteína p53 Supresora de Tumor/genética , Síndrome de Werner/complicaciones , Síndrome de Werner/genéticaRESUMEN
Acute erythroid leukemia (AEL) is a unique subtype of acute myeloid leukemia characterized by prominent erythroid proliferation whose molecular basis is poorly understood. To elucidate the underlying mechanism of erythroid proliferation, we analyzed 121 AEL using whole-genome, whole-exome, and/or targeted-capture sequencing, together with transcriptome analysis of 21 AEL samples. Combining publicly available sequencing data, we found a high frequency of gains and amplifications involving EPOR/JAK2 in TP53-mutated cases, particularly those having >80% erythroblasts designated as pure erythroid leukemia (10/13). These cases were frequently accompanied by gains and amplifications of ERG/ETS2 and associated with a very poor prognosis, even compared with other TP53-mutated AEL. In addition to activation of the STAT5 pathway, a common feature across all AEL cases, these AEL cases exhibited enhanced cell proliferation and heme metabolism and often showed high sensitivity to ruxolitinib in vitro and in xenograft models, highlighting a potential role of JAK2 inhibition in therapeutics of AEL. SIGNIFICANCE: This study reveals the major role of gains, amplifications, and mutations of EPOR and JAK2 in the pathogenesis of pure erythroleukemia. Their frequent response to ruxolitinib in patient-derived xenograft and cell culture models highlights a possible therapeutic role of JAK2 inhibition for erythroleukemia with EPOR/JAK2-involving lesions. This article is highlighted in the In This Issue feature, p. 369.
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Janus Quinasa 2 , Leucemia Eritroblástica Aguda , Leucemia Mieloide Aguda , Receptores de Eritropoyetina , Exoma , Humanos , Janus Quinasa 2/genética , Leucemia Eritroblástica Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/tratamiento farmacológico , Mutación , Pronóstico , Receptores de Eritropoyetina/genéticaRESUMEN
Blast crisis (BC) predicts dismal outcomes in patients with chronic myeloid leukaemia (CML). Although additional genetic alterations play a central role in BC, the landscape and prognostic impact of these alterations remain elusive. Here, we comprehensively investigate genetic abnormalities in 136 BC and 148 chronic phase (CP) samples obtained from 216 CML patients using exome and targeted sequencing. One or more genetic abnormalities are found in 126 (92.6%) out of the 136 BC patients, including the RUNX1-ETS2 fusion and NBEAL2 mutations. The number of genetic alterations increase during the transition from CP to BC, which is markedly suppressed by tyrosine kinase inhibitors (TKIs). The lineage of the BC and prior use of TKIs correlate with distinct molecular profiles. Notably, genetic alterations, rather than clinical variables, contribute to a better prediction of BC prognosis. In conclusion, genetic abnormalities can help predict clinical outcomes and can guide clinical decisions in CML.
Asunto(s)
Crisis Blástica/genética , Evolución Clonal/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Crisis Blástica/tratamiento farmacológico , Crisis Blástica/patología , Proteínas Sanguíneas/genética , Estudios de Cohortes , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Femenino , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Leucemia Mieloide de Fase Crónica/genética , Leucemia Mieloide de Fase Crónica/patología , Masculino , Persona de Mediana Edad , Mutación , Proteínas de Fusión Oncogénica/genética , Pronóstico , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteína Proto-Oncogénica c-ets-2/genética , Secuenciación del Exoma , Adulto JovenRESUMEN
Germline DDX41 mutations were recently reported to cause MDS/AML and donor-derived leukemia after transplantation. While previously described in Western countries, DDX41 variants have not been reported in a Southeast Asian population. We performed targeted sequencing of blood or bone marrow samples from 109 Thai patients with myeloid malignancies. Among the 109 patients (75 MDS, 8 MPN, 11 MDS/MPN and 15 AML), the most frequent mutations were in ASXL1 (17.4%), TET2 (16.5%) and SRSF2 (12.8%), respectively. DDX41 variants were detectable in six (5.5%) cases. Four patients exhibited three presumable germline DDX41 mutations: p.S21fs (n = 2), p.F235fs (n = 1), and p.R339H (n = 1). While p.S21fs was previously reported in myeloid neoplasm, the latter two variants have not been described. Two of these cases harbored concomitant probable germline/somatic DDX41 mutations (p.S21fs/p.R525H and p.R339H/p.K494T), while the other two patients carried only somatic mutations (p.R525H and p.F438L). The p.K494T and p.F438L variants have not been previously reported. In patients with DDX41 alterations, the diagnoses were MDS with excess blasts (4), secondary AML (1) and low-risk MDS (1). In conclusion, we identified DDX41 variants in Thai patients with myeloid malignancies in which these variants could be used to assess predisposition to MDS in Southeast Asia.
Asunto(s)
ARN Helicasas DEAD-box/genética , Leucemia Mieloide/genética , Mutación , Síndromes Mielodisplásicos/genética , Trastornos Mieloproliferativos/genética , Humanos , TailandiaRESUMEN
Mixed-lineage leukemia (MLL) gene rearrangements are among the most frequent chromosomal abnormalities in acute myeloid leukemia (AML). MLL fusion patterns are associated with the patient's prognosis; however, their relationship with driver mutations is unclear. We conducted sequence analyses of 338 genes in pediatric patients with MLL-rearranged (MLL-r) AML (n = 56; JPLSG AML-05 study) alongside data from the TARGET study's pediatric cohorts with MLL-r AML (n = 104), non-MLL-r AML (n = 581), and adult MLL-r AML (n = 81). KRAS mutations were most frequent in pediatric patients with high-risk MLL fusions (MLL-MLLLT10, MLL-MLLT4, and MLL-MLLT1). Pediatric patients with MLL-r AML (n = 160) and a KRAS mutation (KRAS-MT) had a significantly worse prognosis than those without a KRAS mutation (KRAS-WT) (5-year event-free survival [EFS]: 51.8% vs 18.3%, P < .0001; 5-year overall survival [OS]: 67.3% vs 44.3%, P = .003). The adverse prognostic impact of KRAS mutations was confirmed in adult MLL-r AML. KRAS mutations were associated with adverse prognoses in pediatric patients with both high-risk (MLLT10+MLLT4+MLLT1; n = 60) and intermediate-to-low-risk (MLLT3+ELL+others; n = 100) MLL fusions. The prognosis did not differ significantly between patients with non-MLL-r AML with KRAS-WT or KRAS-MT. Multivariate analysis showed the presence of a KRAS mutation to be an independent prognostic factor for EFS (hazard ratio [HR], 2.21; 95% confidence interval [CI], 1.35-3.59; P = .002) and OS (HR, 1.85; 95% CI, 1.01-3.31; P = .045) in MLL-r AML. The mutation is a distinct adverse prognostic factor in MLL-r AML, regardless of risk subgroup, and is potentially useful for accurate treatment stratification. This trial was registered at the UMIN (University Hospital Medical Information Network) Clinical Trials Registry (UMIN-CTR; http://www.umin.ac.jp/ctr/index.htm) as #UMIN000000511.
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Leucemia Mieloide Aguda , Proteínas Proto-Oncogénicas p21(ras) , Adulto , Niño , N-Metiltransferasa de Histona-Lisina/genética , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Mutación , Proteína de la Leucemia Mieloide-Linfoide/genética , Pronóstico , Proteínas Proto-Oncogénicas p21(ras)/genéticaAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Idarrubicina/uso terapéutico , Leucemia Promielocítica Aguda/tratamiento farmacológico , Tretinoina/uso terapéutico , Factores de Edad , Anciano de 80 o más Años , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Idarrubicina/administración & dosificación , Leucemia Promielocítica Aguda/patología , Riesgo , Resultado del Tratamiento , Tretinoina/administración & dosificaciónRESUMEN
Leukemic relapse is frequently accompanied by progressively aggressive clinical course. To understand the molecular mechanism of leukemic relapse, MLL/AF9-transformed mouse leukemia cells were serially transplanted in C57BL/6 mice (N = 96) by mimicking repeated recurrences, where mutations were monitored by exome sequencing (N = 42). The onset of leukemia was progressively promoted with advanced transplants, during which increasing numbers of somatic mutations were acquired (P < 0.005). Among these, mutations in Ptpn11 (p.G60R) and Braf (p.V637E) corresponded to those identified in human MLL-AML, while recurrent mutations affecting Msn (p.R295C) were observed only in mouse but not in human MLL-AML. Another mutated gene of interest was Gnb2 which was reported to be recurrently mutated in various hematological neoplasms. Gnb2 mutations (p.G77R) were significantly increased in clone size (P = 0.007) and associated with earlier leukemia onset (P = 0.011). GNB2 transcripts were significantly upregulated in human MLL-AML compared to MLL-negative AML (P < 0.05), which was supported by significantly increased Gnb2 transcript induced by MLL/AF9 overexpression (P < 0.001). In in vivo model, both mutation and overexpression of GNB2 caused leukemogenesis, and downregulation of GNB2 expression reduced proliferative potential and survival benefit, suggesting a driver role of GNB2. In conclusion, alterations of driver genes over time may play an important role in the progression of MLL-AML.
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N-Metiltransferasa de Histona-Lisina/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Proteína de la Leucemia Mieloide-Linfoide/genética , Animales , Proliferación Celular/genética , Progresión de la Enfermedad , Regulación hacia Abajo/genética , Proteínas de Unión al GTP/genética , Regulación Leucémica de la Expresión Génica/genética , Humanos , Ratones , Ratones Endogámicos C57BL , Mutación/genética , Proteínas de Fusión Oncogénica/genética , Regulación hacia Arriba/genéticaRESUMEN
Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare subtype of peripheral T-cell lymphoma affecting younger patients and associated with hemophagocytic lymphohistiocytosis. To clarify the molecular pathogenesis of SPTCL, we analyzed paired tumor and germline DNAs from 13 patients by whole-exome sequencing. All cases were Asians and were phenotypically sporadic with no family history of SPTCL. Consistent with a recent report, germline mutations in HAVCR2, encoding T-cell immunoglobulin mucin 3 (TIM3), were identified in 11 of 13 (85%) cases. All mutated cases were primary SPTCL, whereas the 2 cases without mutation were secondary SPTCL associated with underlying diseases, including viral infection and autoimmune disease. Ten patients harbored homozygous p.Y82C mutations, and 1 showed compound heterozygous mutations (p.Y82C and p.T101I). Both missense mutations altered highly conserved residues located in the extracellular immunoglobulin variable-like domain. According to the Genome Aggregation Database of >138 500 general individuals, both mutations were documented with minor allele frequencies < 0.007, indicating remarkable enrichment of these HAVCR2 alleles in SPTCL. SPTCL cells also harbored somatic mutations (6.2 per patient) that are frequently identified in genes associated with epigenetic regulation and signal transduction. In conclusion, individuals harboring biallelic HAVCR2 (TIM3) germline mutations were highly susceptible to sporadic SPTCL, which was also associated with clonal somatic mutations.
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Mutación de Línea Germinal , Receptor 2 Celular del Virus de la Hepatitis A/genética , Linfoma de Células T/genética , Paniculitis/genética , Adulto , Alelos , Preescolar , Epigénesis Genética , Humanos , Persona de Mediana Edad , Adulto JovenRESUMEN
POEMS syndrome is a rare paraneoplastic disease associated with monoclonal plasma cells; however, the pathogenic importance of plasma cells remains unclear. We performed comprehensive genetic analyses of plasma cells in 20 patients with POEMS syndrome. Whole exome sequencing was performed in 11 cases and found a total of 308 somatic mutations in 285 genes. Targeted sequencing was performed in all 20 cases and identified 20 mutations in 7 recurrently mutated genes, namely KLHL6, LTB, EHD1, EML4, HEPHL1, HIPK1, and PCDH10. None of the driver gene mutations frequently found in multiple myeloma (MM) such as NRAS, KRAS, BRAF, and TP53 was detected. Copy number analysis showed chromosomal abnormalities shared with monoclonal gammopathy of undetermined significance (MGUS), suggesting a partial overlap in the early development of MGUS and POEMS syndrome. RNA sequencing revealed a transcription profile specific to POEMS syndrome when compared with normal plasma cells, MGUS and MM. Unexpectedly, disease-specific VEGFA expression was not increased in POEMS syndrome. Our study illustrates that the genetic and transcriptional profiles of plasma cells in POEMS syndrome are distinct from MM and MGUS, indicating unique function of clonal plasma cells in its pathogenesis.
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Biomarcadores de Tumor/genética , Perfilación de la Expresión Génica , Mutación , Recurrencia Local de Neoplasia/genética , Síndrome POEMS/genética , Células Plasmáticas/metabolismo , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Masculino , Persona de Mediana Edad , Gammopatía Monoclonal de Relevancia Indeterminada/genética , Gammopatía Monoclonal de Relevancia Indeterminada/patología , Mieloma Múltiple/genética , Mieloma Múltiple/patología , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Síndrome POEMS/tratamiento farmacológico , Síndrome POEMS/patología , Células Plasmáticas/patología , Pronóstico , Secuenciación del Exoma/métodos , Adulto JovenRESUMEN
Peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) is a diagnosis of exclusion, being the most common entity in mature T-cell neoplasms, and its molecular pathogenesis remains significantly understudied. Here, combining whole-exome and targeted-capture sequencing, gene-expression profiling, and immunohistochemical analysis of tumor samples from 133 cases, we have delineated the entire landscape of somatic alterations, and discovered frequently affected driver pathways in PTCL, NOS, with and without a T-follicular helper (TFH) cell phenotype. In addition to previously reported mutational targets, we identified a number of novel recurrently altered genes, such as KMT2C, SETD1B, YTHDF2, and PDCD1. We integrated these genetic drivers using hierarchical clustering and identified a previously undescribed molecular subtype characterized by TP53 and/or CDKN2A mutations and deletions in non-TFH PTCL, NOS. This subtype exhibited different prognosis and unique genetic features associated with extensive chromosomal instability, which preferentially affected molecules involved in immune escape and transcriptional regulation, such as HLA-A/B and IKZF2. Taken together, our findings provide novel insights into the molecular pathogenesis of PTCL, NOS by highlighting their genetic heterogeneity. These results should help to devise a novel molecular classification of PTCLs and to exploit a new therapeutic strategy for this group of aggressive malignancies.
Asunto(s)
Estudios de Asociación Genética , Heterogeneidad Genética , Predisposición Genética a la Enfermedad , Linfoma de Células T Periférico/genética , Alelos , Biomarcadores de Tumor , Biología Computacional , Variaciones en el Número de Copia de ADN , Femenino , Perfilación de la Expresión Génica , Estudios de Asociación Genética/métodos , Variación Genética , Inestabilidad Genómica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Linfoma de Células T Periférico/diagnóstico , Linfoma de Células T Periférico/metabolismo , Masculino , Mutación , Transducción de Señal , Escape del Tumor , Secuenciación del ExomaRESUMEN
In acute myeloid leukemia (AML), MLL (KMT2A) rearrangements are among the most frequent chromosomal abnormalities; however, knowledge of the genetic landscape of MLL-rearranged AML is limited. In this study, we performed whole-exome sequencing (n = 9) and targeted sequencing (n = 56) of samples from pediatric MLL-rearranged AML patients enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group AML-05 study. Additionally, we analyzed 105 pediatric t(8;21) AML samples and 30 adult MLL-rearranged AML samples. RNA-sequencing data from 31 patients published in a previous study were also reanalyzed. As a result, we identified 115 mutations in pediatric MLL-rearranged AML patients (2.1 mutations/patient), with mutations in signaling pathway genes being the most frequently detected (60.7%). Mutations in genes associated with epigenetic regulation (21.4%), transcription factors (16.1%), and the cohesin complex (8.9%) were also commonly detected. Novel CCND3 mutations were identified in 5 pediatric MLL-rearranged AML patients (8.9%) and 2 adult MLL-rearranged AML patients (3.3%). Recurrent mutations of CCND1 (n = 3, 2.9%) and CCND2 (n = 8, 7.6%) were found in pediatric t(8;21) AML patients, whereas no CCND3 mutations were found, suggesting that D-type cyclins exhibit a subtype-specific mutation pattern in AML. Treatment of MLL-rearranged AML cell lines with CDK4/6 inhibitors (abemaciclib and palbociclib) blocked G1 to S phase cell-cycle progression and impaired proliferation. Pediatric MLL-MLLT3-rearranged AML patients with coexisting mutations (n = 16) had significantly reduced relapse-free survival and overall survival compared with those without coexisting mutations (n = 9) (P = .048 and .046, respectively). These data provide insights into the genetics of MLL-rearranged AML and suggest therapeutic strategies.