RESUMEN
BACKGROUND: Blast transformation is a rare but well-recognized event in Philadelphia-negative myeloproliferative neoplasms associated with a poor prognosis. Secondary acute myeloid leukemias evolving from myeloproliferative neoplasms are characterized by a unique set of cytogenetic and molecular features distinct from de novo disease. t(8;21) (q22;q22.1); RUNX1::RUNX1T1, one of the most frequent cytogenetic abnormalities in de novo acute myeloid leukemia, is rarely observed in post-myeloproliferative neoplasm acute myeloid leukemia. Here we report a case of secondary acute myeloid leukemia with t(8;21) evolving from JAK2-mutated essential thrombocythemia. CASE PRESENTATION: The patient was a 74-year-old Japanese woman who was referred because of thrombocytosis (platelets 1046 × 109/L). Bone marrow was hypercellular with increase of megakaryocytes. Chromosomal analysis presented normal karyotype and genetic test revealed JAK2 V617F mutation. She was diagnosed with essential thrombocythemia. Thrombocytosis had been well controlled by oral administration of hydroxyurea; 2 years after the initial diagnosis with ET, she presented with leukocytosis (white blood cells 14.0 × 109/L with 82% of blasts), anemia (hemoglobin 91 g/L), and thrombocytopenia (platelets 24 × 109/L). Bone marrow was hypercellular and filled with 80% of myeloperoxidase-positive blasts bearing Auer rods. Chromosomal analysis revealed t(8;21) (q22;q22.1) and flow cytometry presented positivity of CD 13, 19, 34, and 56. Molecular analysis showed the coexistence of RUNX1::RUNX1T1 chimeric transcript and heterozygous JAK2 V617F mutation in leukemic blasts. She was diagnosed with secondary acute myeloid leukemia with t(8;21)(q22;q22.1); RUNX1::RUNX1T1 evolving from essential thrombocythemia. She was treated with combination chemotherapy with venetoclax and azacytidine. After the first cycle of the therapy, blasts disappeared from peripheral blood and decreased to 1.4% in bone marrow. After the chemotherapy, RUNX1::RUNX1T1 chimeric transcript disappeared, whereas mutation of JAK2 V617F was still present in peripheral leukocytes. CONCLUSIONS: To our best knowledge, the present case is the first one with JAK2 mutation preceding the acquisition of t(8;21). Our result suggests that t(8;21); RUNX1::RUNX1T1 can be generated as a late event in the progression of JAK2-mutated myeloproliferative neoplasms. The case presented typical morphological and immunophenotypic features associated with t(8;21) acute myeloid leukemia.
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Subunidad alfa 2 del Factor de Unión al Sitio Principal , Janus Quinasa 2 , Leucemia Mieloide Aguda , Trombocitemia Esencial , Translocación Genética , Humanos , Femenino , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Anciano , Janus Quinasa 2/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Trombocitemia Esencial/genética , Trombocitemia Esencial/tratamiento farmacológico , Proteína 1 Compañera de Translocación de RUNX1/genética , Cromosomas Humanos Par 8/genética , Cromosomas Humanos Par 21/genética , MutaciónRESUMEN
Introduction: Immunotherapies targeting T cells in solid cancers are revolutionizing clinical treatment. Novel immunotherapies have had extremely limited benefit for acute myeloid leukemia (AML). Here, we characterized the immune microenvironment of t(8;21) AML patients to determine how immune cell infiltration status influenced prognosis. Methods: Through multi-omics studies of primary and longitudinal t(8;21) AML samples, we characterized the heterogeneous immune cell infiltration in the tumor microenvironment and their immune checkpoint gene expression. Further external cohorts were also included in this research. Results: CD8+ T cells were enriched and HAVCR2 and TIGIT were upregulated in the CD34+CD117dim%-High group; these features are known to be associated with immune exhaustion. Data integration analysis of single-cell dynamics revealed that a subset of T cells (cluster_2) (highly expressing GZMB, NKG7, PRF1 and GNLY) evolved and expanded markedly in the drug-resistant stage after relapse. External cohort analysis confirmed that the cluster_2 T-cell signature could be utilized to stratify patients by overall survival outcome. Discussion: In conclusion, we discovered a distinct T-cell signature by scRNA-seq that was correlated with disease progression and drug resistance. Our research provides a novel system for classifying patients based on their immune microenvironment.
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Cromosomas Humanos Par 8 , Leucemia Mieloide Aguda , Análisis de la Célula Individual , Microambiente Tumoral , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Análisis de la Célula Individual/métodos , Pronóstico , Microambiente Tumoral/inmunología , Microambiente Tumoral/genética , Cromosomas Humanos Par 8/genética , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Masculino , Femenino , Translocación Genética , Cromosomas Humanos Par 21/genética , Linfocitos T CD8-positivos/inmunología , Adulto , Persona de Mediana Edad , Biomarcadores de Tumor/genéticaRESUMEN
Chronic myeloid leukemia is defined by the presence of the Philadelphia translocation t (9; 22) resulting in the BCR::ABL1 fusion. The other myeloproliferative neoplasms (MPN) subtypes also carry typical chromosomal abnormalities, which however are not pathognomonic for a specific entity of MPN. According to the WHO classification the distinction between these entities is still based on the integration of cytological, histopathological and molecular findings. Progression of CML into accelerated and blastic phase is usually driven by additional chromosome abnormalities and ABL1 kinase mutations. In the other MPN subtypes the additional mutations besides driver gene mutations in JAK2, MPL and CALR have a decisive impact on the propensity for progression. In addition, the sequence in which the driver mutations and risk conveying additional mutations have been acquired appears to play an important role. Here, we review cytogenetic and molecular changes in CML and MPN that should be evaluated during diagnosis and disease monitoring.
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Janus Quinasa 2 , Leucemia Mielógena Crónica BCR-ABL Positiva , Mutación , Trastornos Mieloproliferativos , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Trastornos Mieloproliferativos/genética , Trastornos Mieloproliferativos/diagnóstico , Trastornos Mieloproliferativos/patología , Janus Quinasa 2/genética , Aberraciones Cromosómicas , Genómica/métodos , Proteínas de Fusión bcr-abl/genética , Receptores de Trombopoyetina/genética , Calreticulina/genética , Translocación GenéticaRESUMEN
BACKGROUND: For myeloid neoplasms with t(7;11)(p15;p15) translocation, the prognosis is quite dismal. Because these tumors are rare, most occurrences are reported as single cases. Clinical results and optimal treatment approaches remain elusive. This study endeavors to elucidate the clinical implications and prognosis of this cytogenetic aberration. METHODS: This study retrospectively analyzed 23 cases of myeloid neoplasm with t(7;11)(p15;p15). Clinicopathological characteristics, genetic alterations, and outcomes were evaluated, and the Kaplan-Meier method was employed to construct survival curves. RESULTS: Of these, nine cases were newly diagnosed acute myeloid leukemia (ND AML), seven presented with relapsed refractory AML (R/R AML), four had myelodysplastic syndrome (MDS), two had secondary AML, and one exhibited a mixed germinoma associated with MDS. Patients with t(7;11)(p15;p15) in AML were primarily younger females who preferred subtype M2. Interestingly, these patients had decreased hemoglobin and red blood cell counts, along with markedly elevated levels of lactic dehydrogenase and interleukin-6, and exhibited the expression of CD117. R/R AML patients exhibited a higher likelihood of additional chromosome abnormalities (ACAs) besides t(7;11). WT1 and FLT3-ITD were the most commonly found mutated genes, and 10 of those instances showed evidence of the NUP98::HOXA9 fusion gene. The composite complete remission rate was 66.7% (12/18), while the cumulative graft survival rate was 100% (4/4). However, the survival outcomes were dismal. Interestingly, the median overall survival for R/R AML patients was 4.0 months (95% CI: 1.7-6.4). Additionally, the type of AML diagnosis or the presence of ACAs or molecular prognostic stratification did not significantly influence clinical outcomes (p = 0.066, p = 0.585, p = 0.570, respectively). CONCLUSION: Myeloid leukemia with t(7;11) exhibits unique clinical features, cytogenetic properties, and molecular genetic characteristics. These survival outcomes were dismal. R/R AML patients have a limited lifespan. For myeloid patients with t(7;11), targeted therapy or transplantation may be an effective course of treatment.
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Cromosomas Humanos Par 11 , Translocación Genética , Humanos , Femenino , Masculino , Estudios Retrospectivos , Adulto , Persona de Mediana Edad , Pronóstico , Cromosomas Humanos Par 11/genética , Adulto Joven , Anciano , Adolescente , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/patología , Cromosomas Humanos Par 7/genética , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/mortalidad , Síndromes Mielodisplásicos/terapiaRESUMEN
The present study described an extremely rare case of acute promyelocytic leukemia (APL) characterized by a complex threeway (15;22;17)(q22;q11.2;q21) translocation. Acute promyelocytic leukemia (APL) is a specific subtype of acute myeloid leukemia with distinctive clinical and therapeutic characteristics. Besides being characterized by the t(15;17)(q22;q12) translocation, this subtype is also notable for its response to all-trans-retinoic acid (ATRA) treatment. APL is highly responsive to a combination of ATRA and chemotherapeutic agents, achieving over 90 % complete remission rates and over 80 % long-term remission rates. In this case, a 79-year-old male patient presented with complaints of weakness, fatigue, and petechial rash, with no other significant medical history except for diabetes mellitus and hypertension. Conventional cytogenetic methods, dual-color dual-fusion, and dual-color break-apart fluorescent in situ hybridization techniques together identified the t(15;22;17) translocation. RT-PCR analysis was performed for expression of PML/RARA fusion transcripts. The patient, diagnosed with APL, exhibited a complete response to all-trans retinoic acid (ATRA) and idarubicin treatment. In this paper, we present the second documented case of t(15;22;17) and explore the remarkable remission observed following treatment with All-Trans Retinoic Acid (ATRA).
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Cromosomas Humanos Par 17 , Leucemia Promielocítica Aguda , Translocación Genética , Humanos , Masculino , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/tratamiento farmacológico , Anciano , Cromosomas Humanos Par 17/genética , Tretinoina/uso terapéutico , Cromosomas Humanos Par 15/genética , Cromosomas Humanos Par 22/genética , Hibridación Fluorescente in SituRESUMEN
T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive mature T-cell malignancy characterized by marked lymphocytosis, B symptoms, lymphadenopathy, and hepatosplenomegaly. There is no standard treatment approach, and in the absence of an allogeneic transplant, the prognosis remains poor. The disease-defining cytogenetic abnormality in T-PLL is the juxtaposition of the TCL1-family oncogene to the TCR gene enhancer locus primarily due to an inversion of chromosome 14, that is, inv(14). The application of next-generation sequencing technologies led to the discovery of highly recurrent gain-of-function mutations in JAK1/3 and STAT5B in over 70% of T-PLL providing opportunities for therapeutic intervention using small molecule inhibitors. Additional genetic mechanisms that may contribute to the pathogenesis of T-PLL remain unknown. Herein we describe the identification of a novel gene fusion SMCHD1::JAK2 resulting from a translocation between chromosome 9 and 18 involving SMCHD1 exon 45 and JAK2 exon 14 (t(9;18)(p24.1;p11.32)(chr9:g.5080171::chr18:g.2793269)), a previously undescribed genetic event in a patient with T-PLL harboring the key disease defining inv(14) resulting in rearrangement of TCL1 and TRA/D. In this manuscript, we describe the clinical and genetic features of the patient's disease course over a 25-month post-treatment duration using ruxolitinib and duvelisib.
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Janus Quinasa 2 , Leucemia Prolinfocítica de Células T , Humanos , Leucemia Prolinfocítica de Células T/genética , Leucemia Prolinfocítica de Células T/tratamiento farmacológico , Leucemia Prolinfocítica de Células T/patología , Janus Quinasa 2/genética , Proteínas de Fusión Oncogénica/genética , Masculino , Translocación Genética , Pirimidinas/uso terapéutico , Pirazoles/uso terapéutico , Persona de Mediana Edad , Nitrilos/uso terapéutico , Cromosomas Humanos Par 9/genéticaAsunto(s)
Amniocentesis , Mosaicismo , Translocación Genética , Humanos , Femenino , Embarazo , Mosaicismo/embriología , Translocación Genética/genética , Adulto , Cromosomas Humanos Par 21/genética , Cromosomas Humanos Par 13/genética , Recién Nacido , Resultado del Embarazo/genética , CariotipificaciónAsunto(s)
Amniocentesis , Mosaicismo , Translocación Genética , Humanos , Femenino , Embarazo , Mosaicismo/embriología , Translocación Genética/genética , Adulto , Cromosomas Humanos Par 4/genética , Cromosomas Humanos Par 10/genética , Recién Nacido , Cariotipificación , Resultado del Embarazo/genéticaRESUMEN
Microphthalmia transcription factor (MiT) family translocation renal cell carcinoma (tRCC) is a rare, aggressive, and heterogeneous subtype of kidney cancer, which is not well characterized. Since genetic alterations are always associated with carcinogenesis, and proteins are the major executors of biological features, multi-omics studies can reveal the systematic tRCC biological process comprehensively. Here, we describe the proteogenomic workflow for characterization of tRCC in detail to provide the knowledge foundation for integrated proteogenomic analysis of tRCC and other malignant tumors in the future.
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Carcinoma de Células Renales , Neoplasias Renales , Factor de Transcripción Asociado a Microftalmía , Proteogenómica , Translocación Genética , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/metabolismo , Humanos , Neoplasias Renales/genética , Proteogenómica/métodos , Factor de Transcripción Asociado a Microftalmía/genética , Factor de Transcripción Asociado a Microftalmía/metabolismo , Flujo de TrabajoRESUMEN
Balanced rearrangements involving the KMT2A gene (KMT2Ar) are recurrent genetic abnormalities in acute myeloid leukemia (AML), but there is lack of consensus regarding the prognostic impact of different fusion partners. Moreover, prognostic implications of gene mutations co-occurring with KMT2Ar are not established. From the HARMONY AML database 205 KMT2Ar adult patients were selected, 185 of whom had mutational information by a panel-based next-generation sequencing analysis. Overall survival (OS) was similar across the different translocations, including t(9;11)(p21.3;q23.3)/KMT2A::MLLT3 (p = 0.756). However, independent prognostic factors for OS in intensively treated patients were age >60 years (HR 2.1, p = 0.001), secondary AML (HR 2.2, p = 0.043), DNMT3A-mut (HR 2.1, p = 0.047) and KRAS-mut (HR 2.0, p = 0.005). In the subset of patients with de novo AML < 60 years, KRAS and TP53 were the prognostically most relevant mutated genes, as patients with a mutation of any of those two genes had a lower complete remission rate (50% vs 86%, p < 0.001) and inferior OS (median 7 vs 30 months, p < 0.001). Allogeneic hematopoietic stem cell transplantation in first complete remission was able to improve OS (p = 0.003). Our study highlights the importance of the mutational patterns in adult KMT2Ar AML and provides new insights into more accurate prognostic stratification of these patients.
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Cromosomas Humanos Par 11 , N-Metiltransferasa de Histona-Lisina , Leucemia Mieloide Aguda , Mutación , Proteína de la Leucemia Mieloide-Linfoide , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Proteína de la Leucemia Mieloide-Linfoide/genética , N-Metiltransferasa de Histona-Lisina/genética , Persona de Mediana Edad , Pronóstico , Adulto , Femenino , Masculino , Cromosomas Humanos Par 11/genética , Anciano , Adulto Joven , Translocación Genética , Reordenamiento Génico , Adolescente , Anciano de 80 o más Años , Tasa de Supervivencia , Secuenciación de Nucleótidos de Alto RendimientoAsunto(s)
Cromosomas Humanos Par 22 , Cromosomas Humanos Par 9 , Leucemia Promielocítica Aguda , Proteínas de Fusión Oncogénica , Translocación Genética , Humanos , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/diagnóstico , Proteínas de Fusión Oncogénica/genética , Cromosomas Humanos Par 22/genética , Cromosomas Humanos Par 9/genética , Masculino , Proteínas Proto-Oncogénicas c-bcr/genética , Femenino , Adulto , Proteína Quinasa 1 Activada por MitógenosRESUMEN
BACKGROUND: Daratumumab's incorporation in the upfront treatment of light chain (AL) amyloidosis has led to daratumumab (dara) refractoriness early in disease course. Patients who experience relapse or have suboptimal response to dara-based-therapy, have limited options. OBJECTIVE: This study aimed to evaluate the outcomes of venetoclax-based therapy in t(11;14) positive AL patients who previously failed dara. METHODS: Thirty-one patients with AL were included in this bi-institutional retrospective analysis. RESULTS: Dara failure was due to inadequate response in 20 (65%) patients, haematologic relapse in 7 (22%), and both haematologic plus organ relapse in 4 (13%). Overall haematologic response rate to venetoclax-based therapy was 97%, with ≥ VGPR being 91%. Of the 19 evaluable patients with cardiac involvement, 14 (74%) achieved organ response. Of the 13 evaluable patients with renal involvement, 6 (46%) achieved organ response. With a median follow-up of 22 months, median time-to-next-treatment (TTNT) and overall survival (OS) were not reached. The 12- and 24-month TTNT rates were 74% and 56%, respectively. At data-cut-off, four patients had died, all from AL-related organ complications. The 12- and 24-month OS rates were 89% and 85%, respectively. Grade ≥3 adverse events occurred in 26% of patients, with 6% due to infections. CONCLUSION: These findings are encouraging for the use of venetoclax as salvage therapy post-dara failure.
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Anticuerpos Monoclonales , Compuestos Bicíclicos Heterocíclicos con Puentes , Cromosomas Humanos Par 14 , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas , Sulfonamidas , Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Sulfonamidas/uso terapéutico , Sulfonamidas/administración & dosificación , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/administración & dosificación , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/tratamiento farmacológico , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/genética , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/mortalidad , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/patología , Estudios Retrospectivos , Cromosomas Humanos Par 14/genética , Cromosomas Humanos Par 11/genética , Adulto , Anciano de 80 o más Años , Translocación Genética , Resultado del Tratamiento , Antineoplásicos/uso terapéuticoRESUMEN
Activation-induced cytidine deaminase (AID) is a B cell-specific mutator required for antibody diversification. However, it is also implicated in the etiology of several B cell malignancies. Evaluating the AID-induced mutation load in patients at-risk for certain blood cancers is critical in assessing disease severity and treatment options. We have developed a digital PCR (dPCR) assay that allows us to quantify mutations resulting from AID modification or DNA double-strand break (DSB) formation and repair at sites known to be prone to DSBs. Implementation of this assay shows that increased AID levels in immature B cells increase genome instability at loci linked to chromosomal translocation formation. This includes the CRLF2 locus that is often involved in translocations associated with a subtype of acute lymphoblastic leukemia (ALL) that disproportionately affects Hispanics, particularly those with Latin American ancestry. Using dPCR, we characterize the CRLF2 locus in B cell-derived genomic DNA from both Hispanic ALL patients and healthy Hispanic donors and found increased mutations in both, suggesting that vulnerability to DNA damage at CRLF2 may be driving this health disparity. Our ability to detect and quantify these mutations will potentiate future risk identification, early detection of cancers, and reduction of associated cancer health disparities.
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Citidina Desaminasa , Hispánicos o Latinos , Mutación , Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores de Citocinas , Humanos , Citidina Desaminasa/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Hispánicos o Latinos/genética , Receptores de Citocinas/genética , Roturas del ADN de Doble Cadena , Linfocitos B/metabolismo , Linfocitos B/inmunología , Disparidades en el Estado de Salud , Translocación Genética , Sitios Genéticos , América Latina , FemeninoRESUMEN
G0-G1 phase alternative end joining (A-EJ) is a recently defined mutagenic pathway characterized by resected deletion and translocation joints that are predominantly direct and are distinguished from A-EJ in cycling cells that rely much more on microhomology-mediated end joining (MMEJ). Using chemical and genetic approaches, we systematically evaluate potential A-EJ factors and DNA damage response (DDR) genes to support this mechanism by mapping the repair fates of RAG1/2-initiated double-strand breaks in the context of Igκ locus V-J recombination and chromosome translocation. Our findings highlight a polymerase theta-independent Parp1-XRCC1/LigIII axis as central A-EJ components, supported by 53BP1 in the context of an Ataxia-telangiectasia mutated (ATM)-activated DDR. Mechanistically, we demonstrate varied changes in short-range resection, MMEJ, and translocation, imposed by compromising specific DDR activities, which include polymerase alpha, Ataxia-telangiectasia and Rad3-related (ATR), DNA2, and Mre11. This study advances our understanding of DNA damage repair within the 53BP1 regulatory domain and the RAG1/2 postcleavage complex.
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Proteínas de la Ataxia Telangiectasia Mutada , Reparación del ADN por Unión de Extremidades , Proteína 1 de Unión al Supresor Tumoral P53 , Recombinación V(D)J , Proteína 1 de Unión al Supresor Tumoral P53/metabolismo , Proteína 1 de Unión al Supresor Tumoral P53/genética , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Proteínas de la Ataxia Telangiectasia Mutada/genética , Animales , Humanos , Roturas del ADN de Doble Cadena , Ratones , Daño del ADN , Translocación GenéticaRESUMEN
When sex chromosomes evolve recombination suppression, the sex-limited chromosome (Y/W) commonly degenerate by losing functional genes. The rate of Y/W degeneration is believed to slow down over time as the most essential genes are maintained by purifying selection, but supporting data are scarce especially for ZW systems. Here, we study W degeneration in Sylvioidea songbirds where multiple autosomal translocations to the sex chromosomes, and multiple recombination suppression events causing separate evolutionary strata, have occurred during the last ~ 28.1-4.5 million years (Myr). We show that the translocated regions have maintained 68.3-97.7% of their original gene content, compared to only 4.2% on the much older ancestral W chromosome. By mapping W gene losses onto a dated phylogeny, we estimate an average gene loss rate of 1.0% per Myr, with only moderate variation between four independent lineages. Consistent with previous studies, evolutionarily constrained and haploinsufficient genes were preferentially maintained on W. However, the gene loss rate did not show any consistent association with strata age or with the number of W genes at strata formation. Our study provides a unique account on the pace of W gene loss and reinforces the significance of purifying selection in maintaining essential genes on sex chromosomes.
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Evolución Molecular , Cromosomas Sexuales , Animales , Cromosomas Sexuales/genética , Masculino , Femenino , Filogenia , Pájaros Cantores/genética , Translocación GenéticaRESUMEN
Duchenne and Becker muscular dystrophies, caused by pathogenic variants in DMD, are the most common inherited neuromuscular conditions in childhood. These diseases follow an X-linked recessive inheritance pattern, and mainly males are affected. The most prevalent pathogenic variants in the DMD gene are copy number variants (CNVs), and most patients achieve their genetic diagnosis through Multiplex Ligation-dependent Probe Amplification (MLPA) or exome sequencing. Here, we investigated a female patient presenting with muscular dystrophy who remained genetically undiagnosed after MLPA and exome sequencing. RNA sequencing (RNAseq) from the patient's muscle biopsy identified an 85% reduction in DMD expression compared to 116 muscle samples included in the cohort. A de novo balanced translocation between chromosome 17 and the X chromosome (t(X;17)(p21.1;q23.2)) disrupting the DMD and BCAS3 genes was identified through trio whole genome sequencing (WGS). The combined analysis of RNAseq and WGS played a crucial role in the detection and characterisation of the disease-causing variant in this patient, who had been undiagnosed for over two decades. This case illustrates the diagnostic odyssey of female DMD patients with complex structural variants that are not detected by current panel or exome sequencing analysis.
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Cromosomas Humanos X , Distrofina , Genómica , Distrofia Muscular de Duchenne , Translocación Genética , Humanos , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/diagnóstico , Femenino , Distrofina/genética , Cromosomas Humanos X/genética , Genómica/métodos , Variaciones en el Número de Copia de ADN , Secuenciación del Exoma , Transcriptoma/genética , Cromosomas Humanos Par 17/genéticaRESUMEN
Endothelial cells (ECs) maintain vessel tone and barrier integrity, regulate blood homeostasis, and prevent the extravasation of leukocytes under normal physiological conditions. Because of the limited lifespans and batch-to-batch differences with respect to the genetic make-up of primary ECs, established immortal EC lines are extensively used for studying endothelial biology. To address this issue, the immortal endothelial cell line EA.hy926 was developed by fusing primary human umbilical vein endothelial cells (HUVECs) with human lung carcinoma A549 cells. EA.hy926 cells share a number of similar endothelial properties with HUVECs and are considered the immortal counterpart to primary HUVECs. However, the cytogenetic integrity of EA.hy926 cells is not fully elucidated. We characterized EA.hy926 cells with conventional G-banding and molecular cytogenetic techniques such as spectral karyotyping and subtelomeric fluorescence in situ hybridization. Cytogenetic analysis revealed an array of numerical and stable structural chromosomal rearrangements including one deletion, one duplication, one isochromosome, seven simple translocations, and five complex translocations in Ea.hy926 cells. These findings will advance comprehension of EA.hy926 cell biology and augment future endothelial studies, specifically in comparison studies between HUVECs and EA.hy926 cells.
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Bandeo Cromosómico , Células Endoteliales de la Vena Umbilical Humana , Hibridación Fluorescente in Situ , Translocación Genética , Humanos , Hibridación Fluorescente in Situ/métodos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Análisis Citogenético/métodos , Células Endoteliales/metabolismo , Aberraciones Cromosómicas , Células A549RESUMEN
A 69-year-old man presented with lumbago and was diagnosed with multiple myeloma (IgD-λ type, R-ISS stage II) with bone-destructive lesions in the lumbar spine and sacrum. Chromosome analysis showed t (8;14)(q24;q32) and t (11;14)(q13;q32). Treatment with daratumumab, lenalidomide, and dexamethasone resulted in partial response, but the disease relapsed, with a copy number increase in t (11;14) and abnormal amplification of the 1q21 region. The patient was treated for CMV enteritis, and was admitted to the hospital due to sudden abdominal pain. Gastrointestinal perforation was diagnosed by CT scan showing free air and wall thickening in the small intestine. Emergency surgery was performed, and the tumors in the perforated area were positive for CCND1 but negative for MYC on immunostaining. The patient's general condition did not improve after the surgery and he died. Pathological autopsy revealed extramedullary infiltration of multiple organs in addition to the small intestine. Extramedullary infiltration is thought to be caused by clonal evolution, and further research is warranted to clarify its pathogenesis and establish effective therapeutic strategies in high-risk patients.