RESUMO

The heterogeneity of Myelodysplastic Neoplasm (MDS) extends beyond mutational diversity to include significant ethnic variability, a factor that has been underexplored. While the development of the IPSS-M prognostic tool has advanced our understanding of MDS, its reliance on data primarily from European cohorts limits its applicability to non-European populations. Duployez et al.'s review highlighted the importance of molecular markers in MDS for personalized treatment and disease monitoring yet did not address the impact of genetic ancestry. This commentary critiques the IPSS-M's limited sample of 110 Brazilian patients, questioning its adequacy in reflecting the influence of patient ancestry on prognostic accuracy. Given the potential for differing mutation profiles and prognostic implications across diverse ethnic groups, robust genomic ancestry studies are urgently needed. These studies should stratify MDS patients by ethnic background to investigate mutation incidence and impacts, thereby validating IPSS-M and potentially identifying new prognostic markers. Incorporating ethnic diversity into prognostic models is essential for ensuring they are truly universal and inclusive, thereby improving personalized treatment and care for all MDS patients. Commentary on: Duployez and Preudhomme. Monitoring molecular changes in the management of myelodysplastic syndromes. Br J Haematol 2024; 205:772-779.

Assuntos

Síndromes Mielodisplásicas , Humanos , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/diagnóstico , Prognóstico , Mutação , Biomarcadores Tumorais/genética

RESUMO

Background: The Molecular International Prognostic Scoring System (IPSS-M) has improved the prediction of clinical outcomes for myelodysplastic syndromes (MDS). The Artificial Intelligence Prognostic Scoring System for MDS (AIPSS-MDS), based on classical clinical parameters, has outperformed the IPSS, revised version (IPSS-R). For the first time, we validated the IPSS-M and other molecular prognostic models and compared them with the established IPSS-R and AIPSS-MDS models using data from South American patients. Methods: Molecular and clinical data from 145 patients with MDS and 37 patients with MDS/myeloproliferative neoplasms were retrospectively analyzed. Results: Prognostic power evaluation revealed that the IPSS-M (Harrell's concordance [C]-index: 0.75, area under the receiver operating characteristic curve [AUC]: 0.68) predicted overall survival better than the European MDS (EuroMDS; C-index: 0.72, AUC: 0.68) and Munich Leukemia Laboratory (MLL) (C-index: 0.70, AUC: 0.64) models. The IPSS-M prognostic discrimination was similar to that of the AIPSS-MDS model (C-index: 0.74, AUC: 0.66) and outperformed the IPSS-R model (C-index: 0.70, AUC: 0.61). Considering simplified low- and high-risk groups for clinical management, after restratifying from IPSS-R (57% and 32%, respectively, hazard ratio [HR]: 2.8; P=0.002) to IPSS-M, 12.6% of patients were upstaged, and 5% were downstaged (HR: 2.9; P=0.001). The AIPSS-MDS recategorized 51% of the low-risk cohort as high-risk, with no patients being downstaged (HR: 5.6; P<0.001), consistent with most patients requiring disease-modifying therapy. Conclusions: The IPSS-M and AIPSS-MDS models provide more accurate survival prognoses than the IPSS-R, EuroMDS, and MLL models. The AIPSS-MDS model is a valid option for assessing risks for all patients with MDS, especially in resource-limited centers where molecular testing is not currently a standard clinical practice.

RESUMO

The myelodysplastic syndrome (MDS) is a heterogeneous group of clonal disorders of hematopoietic progenitor cells related to ineffective hematopoiesis and an increased risk of transformation to acute myelogenous leukemia. MDS is divided into categories, namely lineage dysplasia (MDS-SLD), MDS with ring sideroblasts (MDS-RS), MDS with multilineage dysplasia (MDS-MLD), MDS with excess blasts (MDS-EB). The International Prognostic Classification System (IPSS) ranks the patients as very low, low, intermediate, high, and very high based on disease evolution and survival rates. Evidence points to toll-like receptor (TLR) abnormal signaling as an underlying mechanism of this disease, providing a link between MDS and immune dysfunction. Microbial signals, such as lipopolysaccharides from gram-negative bacteria, can activate or suppress TLRs. Therefore, we hypothesized that MDS patients present gut microbiota alterations associated with disease subtypes and prognosis. To test this hypothesis, we sequenced the 16S rRNA gene from fecal samples of 30 MDS patients and 16 healthy elderly controls. We observed a negative correlation between Prevotella spp. and Akkermansia spp. in MDS patients compared with the control group. High-risk patients presented a significant increase in the genus Prevotella spp. compared to the other risk categories. There was a significant reduction in the abundance of the genus Akkermansia spp. in high-risk patients compared with low- and intermediate-risk. There was a significant decrease in the genus Ruminococcus spp. in MDS-EB patients compared with controls. Our findings show a new association between gut dysbiosis and higher-risk MDS, with a predominance of gram-negative bacteria.

RESUMO

AIM: To comprehensively analyze trends in myelodysplastic neoplasm (MDS) mortality across Spain (1999-2022), examining sex and regional differences. METHODS: We analyzed nationwide death records and population data, calculating age-standardized mortality rates (ASMRs) and standardized mortality ratios (SMRs) stratified by sex and Autonomous Community (AC). Joinpoint regression identified significant shifts in trends. RESULTS: Across Spain, MDS mortality risk varied among men, with rates ranging from 1.08 to 4.38 per 100,000 across regions, while women's rates ranged from 1.23 to 2.02. Five regions had higher risks than the national average, while six had lower risks. Joinpoint analysis revealed three periods nationally: a decline until 2008, and an increase until 2017, followed by a significant decrease. Despite the overall stable national trend (-0.5% annual change), significant regional variations emerged. Andalusia stood out with a worrying increase in MDS mortality, while Aragon and Murcia demonstrated promising declines. Extremadura displayed a unique trajectory with an initial rise followed by stabilization, while Galicia exhibited a contrasting trend with an initial decline and subsequent increase. Notably, men consistently faced a higher risk of MDS mortality compared to women, with significant disparities across regions. Extremadura, in particular, showed a marked difference in risk between genders. CONCLUSION: MDS mortality trends in Spain are complex, and influenced by gender, region, and time. Further research is needed to understand regional disparities, recent national decline, and higher risk in specific demographics. Tailored interventions based on local factors and targeted research are crucial to address these complexities and improve patient outcomes.

Assuntos

Síndromes Mielodisplásicas , Humanos , Espanha/epidemiologia , Síndromes Mielodisplásicas/mortalidade , Feminino , Masculino , Idoso , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Fatores Sexuais , Mortalidade/tendências , Adulto

RESUMO

To assess and validate the gene expression profile of SIRTs (SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, and SIRT7) in relation to the pathogenesis and prognostic progression of Myelodysplastic neoplasm (MDS). Eighty bone marrow samples of patients with de novo MDS were diagnosed according to WHO 2022 and IPSS-R criteria. Ten bone marrow samples were obtained from elderly healthy volunteers and used as control samples. Gene expression levels of all SIRTs were assessed using RT-qPCR assays. Downregulation of SIRT2 (p = 0.009), SIRT3 (p = 0.048), SIRT4 (p = 0.049), SIRT5 (p = 0.046), SIRT6 (p = 0.043), and SIRT7 (p = 0.047) was identified in MDS patients compared to control individuals. Also, we identified that while SIRT2-7 genes are typically down-regulated in MDS patients compared to normal controls, there are relative expression variations among MDS patient subgroups. Specifically, SIRT4 (p = 0.029) showed increased expression in patients aged 60 or above, and both SIRT2 (p = 0.016) and SIRT3 (p = 0.036) were upregulated in patients with hemoglobin levels below 8 g/dL. SIRT2 (p = 0.045) and SIRT3 (p = 0.033) were highly expressed in patients with chromosomal abnormalities. Different SIRTs exhibited altered expression patterns concerning specific MDS clinical and prognostic characteristics. The downregulation in SIRTs genes (e.g., SIRT2 to SIRT7) expression in Brazilian MDS patients highlights their role in the disease's development. The upregulation of SIRT2 and SIRT3 in severe anemia patients suggests a potential link to manage iron overload-related complications in transfusion-dependent patients. Moreover, the association of SIRT2/SIRT3 with genomic instability and their role in MDS progression signify promising areas for future research and therapeutic targets. These findings underscore the importance of SIRT family in understanding and addressing MDS, offering novel clinical, prognostic, and therapeutic insights for patients with this condition.

Assuntos

Proteínas Mitocondriais , Síndromes Mielodisplásicas , Sirtuína 3 , Sirtuínas , Humanos , Sirtuínas/genética , Sirtuínas/metabolismo , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/genética , Prognóstico , Sirtuína 3/genética , Sirtuína 3/metabolismo , Sirtuína 2/genética , Sirtuína 2/metabolismo , Adulto , Idoso de 80 Anos ou mais , Sirtuína 1/genética , Sirtuína 1/metabolismo , Regulação Neoplásica da Expressão Gênica , Perfilação da Expressão Gênica/métodos , Estudos de Casos e Controles

RESUMO

Background: Pediatric myelodysplastic syndrome (pMDS) is a group of rare clonal neoplasms with a difficult diagnosis and risk of progression to acute myeloid leukemia (AML). The early stratification in risk groups is essential to choose the treatment and indication for allogeneic hematopoietic stem cell transplantation (HSCT). According to the Revised International Prognostic Scoring System, cytogenetic analysis has demonstrated an essential role in diagnosis and prognosis. In pMDS, abnormal karyotypes are present in 30-50% of the cases. Monosomy 7 is the most common chromosomal alteration associated with poor prognosis. However, the rarity of specific cytogenetic alterations makes its prognosis uncertain. Thus, this study aimed to describe uncommon cytogenetic alterations in a cohort of 200 pMDS patients and their association with evolution to AML. Methods: The cytogenetic analysis was performed in 200 pMDS patients by G-banding and fluorescence in situ hybridization between 2000 to 2022. Results: Rare chromosome alterations were observed in 7.5% (15/200) of the cases. These chromosome alterations were divided into four cytogenetic groups: hyperdiploidy, biclonal chromosomal alterations, translocations, and uncommon deletions representing 33.3%, 33.3%, 20%, and 13.3%, respectively. Most of these patients (10/15) were classified with advanced MDS (MDS-EB and MDS/AML) and the initial subtype was present in five patients (RCC). The leukemic evolution was observed in 66.66% (10/15) of the patients. Most patients had poor clinical outcomes and they were indicated for HSCT. Conclusion: The study of uncommon cytogenetic alterations in pMDS is important to improve the prognosis and guide early indication of HSCT.

RESUMO

OBJECTIVE: The present study aims to assess the mortality trends in myelodysplastic syndromes (MDS) in Spain from 1980 to 2021. METHODS: Deaths and mid-year population data were collected from the National Institute of Statistics. We estimated age-standardised mortality rates (ASMRs) per 100,000 person-years for all ages and ages 35-64. Joinpoint regression identified significant changes in mortality trends. The independent effects of age, period and birth cohort on MDS mortality were also examined. RESULTS: MDS-related deaths gradually increased from 36 in 1980 to 1118 in 2021, with an overall increase of 6.6% in age-standardised mortality rates (ASMRs) for both men and women. Joinpoint analysis identified four periods for both men and women: 1980-1987 (stable rates), 1987-1990 (sharp increase), 1990-1999 (slower increase) and 1999-2021 (stable rates). ASMRs (35-64 years) increased by 2.5% over the study period, with a turning point identified in 1996 when rates decreased. Mortality from MDS increases with age and is higher in men. The cohort's relative risk increased until the mid-1950s and then stabilised, whilst the period relative risk increased between 1982 and 1996 and then stabilised. CONCLUSION: The results of this study indicate a progressive increase in MDS-related deaths in Spain between 1980 and 2021. Notably, this increase was more pronounced in men than in women. Analysis of birth cohort trends revealed shifts in MDS risk, characterised by an increase until the mid-twentieth century, followed by a stabilisation. Using joinpoint analysis, four distinct periods were identified, shedding light on the changing patterns of mortality over time. These findings help to shape future research directions and inform public health strategies. They also provide optimism for advances in MDS treatment and potential reductions in mortality.

Assuntos

Síndromes Mielodisplásicas , Procedimentos de Cirurgia Plástica , Masculino , Humanos , Feminino , Espanha/epidemiologia , Mortalidade

RESUMO

The aim of the present study was to investigate the relationship between leptin and adiponectin gene polymorphisms, circulating levels of leptin and adiponectin, adiposity and clinical markers in patients with myelodysplastic syndrome (MDS). This cross-sectional study was conducted with 102 adults and elderly MDS patients and 102 age- and sex-matched controls. Clinical characteristics, co-morbidities, anthropometric data, laboratory evaluation and genetic analysis (polymorphisms -2548G > A/rs7799039 of the LEP gene and +276G > T/rs1501299 of the ADIPOQ gene) were investigated. Serum leptin was higher and adiponectin lower in MDS when compared with controls. There was a significant positive correlation between serum leptin levels and BMI (r = 0·264, P = 0·025), waist circumference (r = 0·235, P = 0·047), body fat percentage (BF %) (r = 0·373, P = 0·001) and the fat mass index (FMI) (r = 0·371, P < 0·001). A lower mean adiponectin was found among patients with high BF %, higher visceral adiposity index and metabolic syndrome. A significant association was found between the AA genotype (mutant) of the LEP polymorphism rs7799039 and male sex and blast excess (≥ 5 %). In addition, a significant association was observed between the TT genotype (mutant) of the ADIPOQ rs1501299 polymorphism and Fe overload. These results demonstrate the importance of a comprehensive and systematic evaluation in patients with MDS in order to identify and control negative factors not related to the disease at an early stage.

Assuntos

Leptina , Síndromes Mielodisplásicas , Adulto , Idoso , Humanos , Masculino , Adipocinas , Adiponectina/genética , Adiposidade/genética , Estudos Transversais , Leptina/genética , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/complicações , Obesidade/complicações , Polimorfismo de Nucleotídeo Único

RESUMO

BACKGROUND: Anemia exhibits complex causation mechanisms and genetic heterogeneity. Some cases result in poor outcomes with multisystemic dysfunction, including renal tubulopathy. Early diagnosis is crucial to improve management. CASE-DIAGNOSIS/TREATMENT: A 21-month-old female patient was admitted with severe anemia. Persistent neutropenia and dysplastic signs suggested myelodysplastic syndrome, but targeted gene panel results were negative. After multiple transfusions, spontaneous hematologic recovery was observed. At 4 years old, she presented failure to thrive, renal Fanconi syndrome, and severe metabolic acidosis. Differential diagnosis included Pearson syndrome (PS), a life-threatening condition associated with mitochondrial DNA (mtDNA), featuring anemia and pancreatic insufficiency. Further analysis revealed a ~ 7.5 kb mtDNA deletion. Until the age of 5, supportive care has been provided, without pancreatic insufficiency. CONCLUSIONS: This PS case highlights the importance of genetic testing, even in the absence of typical features. Understanding the nature of mitochondrial disorders enables treatment tailoring and counseling about the prognosis.

Assuntos

Anemia , Insuficiência Pancreática Exócrina , Doenças Mitocondriais , Síndromes Mielodisplásicas , Lactente , Humanos , Feminino , Pré-Escolar , Doenças Mitocondriais/complicações , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , DNA Mitocondrial/genética , Anemia/diagnóstico , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética

RESUMO

ABSTRACT Introduction: Immune checkpoints are regulators of the immune system response that allow self-tolerance. Molecules such as Programmed Cell Death Protein 1 (PD-1) and its Ligand (PD-L1) participate in the immune checkpoint by signaling co-inhibition of lymphocyte responses. In cancers, PD-L1 expression is associated with the immune evasion mechanism, which favors tumor growth. The use of anti-PD-1/PD-L1 drugs is already well described in solid tumors, but still not fully understood in hematologic malignancies. Myelodysplastic neoplasms (MDSs) are heterogeneous bone marrow disorders with an increased risk of progression to Acute Myeloid Leukemia (AML). The MDS affects hematopoietic stem cells and its pathogenesis is linked to genetic and epigenetic defects, in addition to immune dysregulation. The influence of the PD-L1 on the MDS remains unknown. Methods: In this study, we evaluated the mRNA expression of the PD-L1 in 53 patients with MDS, classified according to the WHO 2016 Classification. Results: Patients with dyserythropoiesis presented significantly higher PD-L1 expression than patients without dyserythropoiesis (p = 0.050). Patients classified as having MDS with an excess of blasts 2 (MDS-EB2) presented a significant upregulation in the mRNA expression of the PD-L1 compared to the MDS with an excess of blasts 1 (MDS-EB1) (p = 0.050). Furthermore, we detected three patients with very high levels of PD-L1 expression, being statistically classified as outliers. Conclusion: We suggested that the high expression of the PD-L1 is associated with a worse prognosis in the MDS and functional studies are necessary to evaluate the possible use of anti-PD-L1 therapies for high-risk MDS, such as the MDS-EBs.

Assuntos

Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Síndromes Mielodisplásicas , Neoplasias , Evasão da Resposta Imune , Proteína 2 Ligante de Morte Celular Programada 1

RESUMO

Background: Acute myeloid leukemia (AML) is characterized by the presence of ≥ 20% myeloblasts in peripheral blood or bone marrow, as well as specific cytogenetic alterations. It can appear as a de novo disease or be associated with other hematologic diseases, which is why the clinical presentation is heterogeneous. Pancytopenia as a manifestation of aleukemic leukemia is a rare entity. Here, we described a case of AML that presented with pancytopenia as the only manifestation in a secondary care center. Clinical case: 72-year-old man, hospitalized due to pancytopenia, with no history of hematological diseases, asymptomatic, without hepatosplenomegaly or bleeding. Flow cytometry revealed pancytopenia without blasts in peripheral blood. Secondary causes of pancytopenia as infections, splenomegaly and nutritional deficiencies where ruled out. Bone marrow aspirate showed infiltration by 45% of myeloblasts and myelodysplasia. Immunophenotype was compatible with AML. Patient was sent to the Hematology Department at Centro Médico Nacional Siglo XXI (21st Century National Medical Center) to start chemotherapy. Conclusions: AML that is presented as pancytopenia should be considered in the evaluation of marrow failure syndrome. In the context of our hospital, morphological findings remains an essential tool for early diagnosis, since more refined studies such as immunophenotyping and cytogenetic testing are unreachable in a timely manner.

---

Introducción: La leucemia mieloide aguda (LMA) se caracteriza por presentar ≥ 20% de mieloblastos en sangre periférica o médula ósea, así como alteraciones citogenéticas específicas. Surge como enfermedad de novo o asociada a trastornos hematológicos, por lo que la presentación clínica es heterogénea. La presentación como pancitopenia (leucemia aleucémica) es rara. El objetivo de este trabajo es presentar un caso de LMA que cursó con pancitopenia como única manifestación clínica en un hospital de segundo nivel de atención. Caso clínico: hombre de 72 años, hospitalizado por hallazgo de pancitopenia, sin historial de enfermedades hematológicas, asintomático, sin adenomegalias ni hemorragia. La citometría hemática documentó pancitopenia sin blastos en sangre periférica. Se descartaron causas secundarias como infección, esplenomegalia y deficiencias nutricionales. En el aspirado de médula ósea se observó 45% de mieloblastos y mielodisplasia. El inmunofenotipo fue compatible con LMA. El paciente fue referido a Hematología del Centro Médico Nacional Siglo XXI para iniciar quimioterapia. Conclusiones: la LMA que se presenta como pancitopenia debe ser tomada en cuenta en el protocolo diagnóstico de síndrome de falla medular. En el contexto de nuestro hospital, la morfología hematológica sigue siendo una herramienta indispensable para el diagnóstico temprano de este tipo de enfermedades, ya que estudios más sofisticados, como el inmunofenotipo y la citogenética, no se encuentran disponibles de forma oportuna.

Assuntos

Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Pancitopenia , Masculino , Humanos , Idoso , Pancitopenia/etiologia , Pancitopenia/complicações , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicas/genética

RESUMO

INTRODUCTION: Immune checkpoints are regulators of the immune system response that allow self-tolerance. Molecules such as Programmed Cell Death Protein 1 (PD-1) and its Ligand (PD-L1) participate in the immune checkpoint by signaling co-inhibition of lymphocyte responses. In cancers, PD-L1 expression is associated with the immune evasion mechanism, which favors tumor growth. The use of anti-PD-1/PD-L1 drugs is already well described in solid tumors, but still not fully understood in hematologic malignancies. Myelodysplastic neoplasms (MDSs) are heterogeneous bone marrow disorders with an increased risk of progression to Acute Myeloid Leukemia (AML). The MDS affects hematopoietic stem cells and its pathogenesis is linked to genetic and epigenetic defects, in addition to immune dysregulation. The influence of the PD-L1 on the MDS remains unknown. METHODS: In this study, we evaluated the mRNA expression of the PD-L1 in 53 patients with MDS, classified according to the WHO 2016 Classification. RESULTS: Patients with dyserythropoiesis presented significantly higher PD-L1 expression than patients without dyserythropoiesis (p = 0.050). Patients classified as having MDS with an excess of blasts 2 (MDS-EB2) presented a significant upregulation in the mRNA expression of the PD-L1 compared to the MDS with an excess of blasts 1 (MDS-EB1) (p = 0.050). Furthermore, we detected three patients with very high levels of PD-L1 expression, being statistically classified as outliers. CONCLUSION: We suggested that the high expression of the PD-L1 is associated with a worse prognosis in the MDS and functional studies are necessary to evaluate the possible use of anti-PD-L1 therapies for high-risk MDS, such as the MDS-EBs.

RESUMO

ABSTRACT Introduction: The data on the pattern of primary hematologic malignancies in Bahrain is sparse, although previously published studies suggested rising trends in their incidence. This study aimed to compare with regional and world data and identify any changing trends. Methods: A retrospective cross-sectional chart analysis study was done on all cases of primary hematologic malignancies of bone marrow origin of Bahraini nationals presenting during the 10-year period from January 2005 to December 2014 at the sole oncology referral center in Bahrain during the study period. Results: In a total of 272 cases, the primary hematologic malignancies in decreasing order of frequency with respective median ages at diagnosis were: acute myeloid leukemia (AML; 26.1%, 39 years), acute lymphoblastic leukemia (ALL; 22.8%, 9 years), multiple myeloma (MM, 16.2%, 57 years), chronic myeloid leukemia (CML, 14%, 39.5 years), myelodysplastic syndromes (MDS; 12.5%, 56 years) and chronic lymphocytic leukemia (CLL; 5.5%, 65 years). The overall crude annual incidence rate of these malignancies was 4.8/105 population. Age-specific incidence rates were found to increase dramatically with age, except for ALL, for which it peaked in the pediatric age group. The age-standardized incidence rates (ASIRs) per 105 per year were 1.47 (AML), 1.13 (MM), 0.93 (ALL), 0.85 (MDS), 0.81 (CML) and 0.44 (CLL). Conclusion: The pattern of primary hematologic malignancies in Bahrain shows unique features that distinguish it from trends reported in Eastern and Western world populations.

RESUMO

The aim of this study was to evaluate the expression of USP7, USP15, UBE2O, and UBE2T genes in Myelodysplastic neoplasm (MDS) to identify possible targets of ubiquitination and deubiquitination in MDS pathobiology. To achieve this, eight datasets from the Gene Expression Omnibus (GEO) database were integrated, and the expression relationship of these genes was analyzed in 1092 MDS patients and healthy controls. Our results showed that UBE2O, UBE2T, and USP7 were upregulated in MDS patients compared with healthy individuals, but only in mononucleated cells collected from bone marrow samples (p < 0.001). In contrast, only the USP15 gene showed a downregulated expression compared with healthy individuals (p = 0.03). Additionally, the upregulation of UBE2T expression was identified in MDS patients with chromosomal abnormalities compared with patients with normal karyotypes (p = 0.0321), and the downregulation of UBE2T expression was associated with MDS hypoplastic patients (p = 0.033). Finally, the USP7 and USP15 genes were strongly correlated with MDS (r = 0.82; r2 = 0.67; p < 0.0001). These findings suggest that the differential expression of the USP15-USP7 axis and UBE2T may play an important role in controlling genomic instability and the chromosomal abnormalities that are a striking characteristic of MDS.

Assuntos

Síndromes Mielodisplásicas , Neoplasias , Humanos , Peptidase 7 Específica de Ubiquitina/genética , Síndromes Mielodisplásicas/patologia , Aberrações Cromossômicas , Ubiquitinação , Enzimas de Conjugação de Ubiquitina/genética , Enzimas de Conjugação de Ubiquitina/metabolismo , Proteases Específicas de Ubiquitina/genética , Proteases Específicas de Ubiquitina/metabolismo

RESUMO

BACKGROUND: Childhood myelodysplastic neoplasm (cMDS) often raises concerns about an underlying germline predisposition, and its verification is necessary to guide therapeutic choice and allow family counseling. Here, we report a novel constitutional t(3;8)(p26;q21) in a child with MDS, inherited from the father, the ANKRD26 and SRP72 variants from the maternal origin, and the acquisition of molecular alterations during MDS evolution. CASE PRESENTATION: A 4-year-old girl showed repeated infections and severe neutropenia. Bone marrow presented hypocellularity with dysplastic features. The patient had a t(3;8)(p26;q21)c identified by G-banding and FISH analysis. The family nucleus investigation identified the paternal origin of the chromosomal translocation. The NGS study identified ANKRD26 and SRP72 variants of maternal origin. CGH-array analysis detected alterations in PRSS3P2 and KANSL genes. Immunohistochemistry showed abnormal p53 expression during the MDS evolution. CONCLUSION: This study shows for the first time, cytogenetic and genomic abnormalities inherited from the father and mother, respectively, and their clinical implications. It also shows the importance of investigating patients with constitutional cytogenetic alterations and/or germline variants to provide information to their family nucleus for genetic counseling and understanding of the pathogenesis of childhood MDS.

RESUMO

PURPOSE: To investigate the value of red blood cell parameters in Myelodysplastic syndrome (MDS) diagnosis and their relations to MDS subtypes and risk groups. METHODS: The red blood cell parameter [mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC) and red cell distribution width (RDW)] levels [203 MDS, 99 aplastic anemia (AA), 145 megaloblastic anemia (MA)] were collected from a single-center retrospective cohort. The cut-off values, area under the receiver operating characteristic curve (ROC) curve (AUC), sensitivity and specificity of the four parameters were calculated from the ROC. Furthermore, Kruskal-Wallis test and Dunn's Test were performed to determine erythrocyte parameters in different subtypes and prognostic risks MDS. RESULTS: There are significant statistic differences in RDW (P < 0.001), MCH (P = 0.036) and MCHC (P < 0.001) (MDS vs AA); RDW (P = 0.009), MCV (P < 0.001), MCH (P < 0.001) and MCHC (P = 0.001) (MDS vs MA); MCV (P = 0.011) and MCH (P = 0.008) (higher-risk MDS vs lower-risk MDS). Between MDS and MA, the area under the receiver operating characteristic curve (ROC) curve (AUC) values of MCV, MCH, MCHC, RDW were 0.846, 0.855, 0.617, and 0.593. Between MDS and AA, the AUC values of MCH, MCHC, RDW were 0.609, 0.671, and 0.662, respectively. CONCLUSIONS: The red blood cell parameters contribute to the differential diagnosis of MDS, AA and MA and are related to MDS subtypes and risk groups.

Assuntos

Eritrócitos , Síndromes Mielodisplásicas , Humanos , Estudos Retrospectivos , Índices de Eritrócitos , Síndromes Mielodisplásicas/diagnóstico , Prognóstico

RESUMO

Nucleotide excision repair pathway (NER) is an essential mechanism for single-strand breaks (SSB) repair while xeroderma pigmentosum family (XPA to XPG) is the most important system to NER. Myelodysplastic syndrome (MDS) is a heterogeneous hematological cancer characterized by cytopenias and risk of acute myeloid leukemia (AML) transformation. MDS pathogenesis has been associated with problems of DNA repair system. This report aimed to evaluate NER polymorphisms (XPA rs1800975, XPC rs2228000, XPD rs1799793 and XPF rs1800067) in 269 MDS patients of different populations in Latin America (173 Brazilian and 96 Argentinean). Genotypes were identified in DNA samples by RT-qPCR using TaqMan SNP Genotyping Assay. Regarding rs1799793 polymorphism of XPD for Brazilian population, the heterozygous genotype AG presented a high odds ratio (OR) to have a normal karyotype (p = 0.012, OR=3.000) and the mutant homozygous genotype AA was associated to a high OR of AML transformation (p = 0.034, OR=7.4). In Argentine population, the homozygous mutant AA genotype of rs1800975 polymorphism of XPA was associated with an increased odd to have hemoglobin levels below 8g/dL (p = 0.013, OR=10.000) while for the rs1799793 polymorphism of XPD, the heterozygous AG genotype decreased OR to be classified as good (p < 0.001, OR=9.05 × 10-10), and intermediate (p < 0.001, OR=3.08 × 10-10), according to Revised-International Prognostic Scoring System. Regarding the rs1800067 polymorphisms of XPF, the homozygous mutant AA genotype showed a decreased OR to be classified as good (p < 0.001, OR=4.03 × 10-13) and intermediate (p < 0.001, OR=2.54 × 10-13). Our report reinforces the heterogeneity of MDS and demonstrates the importance of ethnic differences and regional influences in pathogenesis and prognosis of MDS.

RESUMO

Myelodysplastic syndrome (MDS) consists of a group of hematologic tumors that are derived from the clonal proliferation of hematopoietic stem cells, featuring abnormal hematopoietic cell development and ineffective hematopoiesis. Animal models are an important scientific research platform that has been widely applied in the research of human diseases, especially tumors. Animal models with MDS can simulate characteristic human genetic variations and tumor phenotypes. They also provide a reliable platform for the exploration of the pathogenesis and diagnostic markers of MDS as well as for a drug efficacy evaluation. This paper reviews the research status of three animal models and a new spontaneous mouse model with MDS.

Assuntos

Neoplasias Hematológicas , Síndromes Mielodisplásicas , Animais , Camundongos , Humanos , Síndromes Mielodisplásicas/genética , Células-Tronco Hematopoéticas/patologia , Modelos Animais de Doenças , Hematopoese

RESUMO

INTRODUCTION: The data on the pattern of primary hematologic malignancies in Bahrain is sparse, although previously published studies suggested rising trends in their incidence. This study aimed to compare with regional and world data and identify any changing trends. METHODS: A retrospective cross-sectional chart analysis study was done on all cases of primary hematologic malignancies of bone marrow origin of Bahraini nationals presenting during the 10-year period from January 2005 to December 2014 at the sole oncology referral center in Bahrain during the study period. RESULTS: In a total of 272 cases, the primary hematologic malignancies in decreasing order of frequency with respective median ages at diagnosis were: acute myeloid leukemia (AML; 26.1%, 39 years), acute lymphoblastic leukemia (ALL; 22.8%, 9 years), multiple myeloma (MM, 16.2%, 57 years), chronic myeloid leukemia (CML, 14%, 39.5 years), myelodysplastic syndromes (MDS; 12.5%, 56 years) and chronic lymphocytic leukemia (CLL; 5.5%, 65 years). The overall crude annual incidence rate of these malignancies was 4.8/105 population. Age-specific incidence rates were found to increase dramatically with age, except for ALL, for which it peaked in the pediatric age group. The age-standardized incidence rates (ASIRs) per 105 per year were 1.47 (AML), 1.13 (MM), 0.93 (ALL), 0.85 (MDS), 0.81 (CML) and 0.44 (CLL). CONCLUSION: The pattern of primary hematologic malignancies in Bahrain shows unique features that distinguish it from trends reported in Eastern and Western world populations. Compared to previously published reports, ASIR trends decreased in CML and ALL but increased in MDS and MM.