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1.
Br J Haematol ; 204(4): 1249-1261, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38098201

RESUMO

Tyrosine kinase inhibitors (TKIs) have drastically improved the outcomes of pCML (paediatric CML) but data on long-term off-target toxicities of TKIs in children are scarce. In this single-centre, retrospective cum prospective study of pCML in chronic phase, we report our experience of treating 173 children with imatinib and following them for long-term toxicities. Mean (SD) time to attain CHR, CCyR and MMR were 3.05 (2.1), 10.6 (8.4) and 43.4 (31.8) months respectively. DMR was not attained in 59 (34%) patients at last follow-up. Ten patients were switched to second-generation TKIs (2G-TKIs; nilotinib = 1/dasatinib = 9) due to poor/loss in response, of which seven had kinase domain mutations. Three patients progressed to the blastic phase. At a median follow-up of 84 (3-261) months, the 5-year EFS and OS for the entire cohort were 96.9% (95% CI: 93.4-100) and 98.7% (95% CI: 96.9-100) respectively. Screening for long-term toxicities revealed low bone density and hypovitaminosis D in 70% and 80% respectively. Other late effects included short stature (27%), delayed puberty (15%), poor sperm quality (43%) and miscellaneous endocrinopathies (8%). Children younger than 5 years at diagnosis were more susceptible to growth and endocrine toxicities (p = 0.009). Regular monitoring for long-term toxicities, timely intervention and trial of discontinuation whenever feasible are likely to improve the long-term outlook of pCML.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Criança , Humanos , Masculino , Dasatinibe , Seguimentos , Hospitais , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Estudos Prospectivos , Inibidores de Proteínas Quinases/efeitos adversos , Estudos Retrospectivos , Sêmen , Resultado do Tratamento , Pré-Escolar
2.
Mol Biol Rep ; 50(1): 235-244, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36322239

RESUMO

BACKGROUND: Myelodysplastic syndromes (MDS) is defined as heterogenous disease, it contains heterogenous leukemic stem cells with various degree of cell differentiation. The perturbation of genes involved in myeloid progenitor cell growth, differentiation and proliferation lead to morphologic dysplasia, maturation arrest, ineffective hematopoiesis hence the cytopenias and propensity to develop into acute myeloid leukemia (AML). Heterogeneous subsets of MDS patients have been defined by their clinical and biologic abnormalities. These different features lead to the development of different prognostic system; however, these approaches are limited in predicting clinical course, and management of patients remains challenging given the uncertainty of the time course of disease progression. It is of importance to identify transcriptomic marker causing maturational and differentiation arrest which could help in understanding the pathogenesis of disease. METHODS AND RESULTS: We have studied differential gene expression profiles (GEPs) in CD34 + marrow cells from myelodysplastic syndrome (MDS) patients (n = 14) and control CD34 + cells using Affymetrix Human Clariom S microarray with 20,000 well annotated genes. We found 4165 genes significantly (p < 0.05) differentially expressed in MDS. Using stringent bioinformatics analyses, we were able to identify few genes (MAPK8, JUNB, mTOR) which were differentially upregulated i.e. 5.39, 73.61 and 2.7 fold change observed in MDS than control and also validated (n = 60) these genes by RT - qPCR. Kaplan - Meier survival analysis indicated that MAPK8 and JUNB could be poor prognostic marker as patients with increased expression showed poor survival, whereas surprisingly mTOR increased expression proved to be good prognostic marker. The correlation analysis showed that the level of gene (MAPK8, JUNB, mTOR) expression was significantly (p ≤ 0.05) associated with frequency of genetic lesions. Interestingly the increased expression of MAPK8 was significantly accompanied with ASXL1 gene mutation. CONCLUSION: Our study showed an elevation of TNF and AMPK signalling pathways in MDS. TNF signalling might be mediating the proliferative advantage to myeloid clonal cells (mutation carrying cells) over normal cells, whereas, AMPK signalling could be acting as protector against it (favouring normal cells). Hence it would be interesting to explore the functions and pathways associated with mTOR, AMPK, MAPK8 and JUNB in myelopoiesis related diseases like MDS.


Assuntos
Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Humanos , Proteínas Quinases Ativadas por AMP , Síndromes Mielodisplásicas/genética , Leucemia Mieloide Aguda/metabolismo , Medula Óssea/metabolismo , Serina-Treonina Quinases TOR/genética
3.
Mol Biol Rep ; 48(3): 2519-2525, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33778919

RESUMO

Fanconi anemia (FA) occurs due to genomic instability with predisposition to bone marrow failure, phenotypic abnormalities and cancers. Though mutations in 22 genes leading to DNA repair defect have been identified, the cellular factor such as oxidative stress has also shown to be associated with FA. Nitrosative Stress (NS) is biochemically correlated to many oxidative stress related disorders and the NS as a pathological hallmark in FA has been so far overlooked. We carried out the study first time in Indian patients with FA with an objective to understand the role of NS in the pathogenesis of FA. The study was carried out in 70 FA subjects. The FA subjects were diagnosed by chromosomal breakage analysis. Molecular study was carried out by Next Generation Sequencing and Sanger sequencing. The 3-nitrotyrosine [3-NT] levels were estimated through enzyme-linked immuno-sorbent assay (ELISA) and the nitric oxide synthase genes- NOS1 (c.-420-34221G>A (rs1879417), c.-420-10205C>T (rs499776), c.4286+720G>C (rs81631)) and NOS2 (c.1823C>T (p. Ser608Leu) (rs2297518)) polymorphism were studied by direct sequencing. Chromosomal breakage analysis revealed a high frequency of chromosomal breaks (Mean chromosomal breakage-4.13 ± 1.5 breaks/metaphase) in 70 FA patients as compared to the control. Molecular studies revealed FANCA (58.34%), FANCG (18.34%) and FANCL (16.6%) complementation groups. The 3-nitrotyrosine [3-NT] levels showed to be significantly (p < 0.05) elevated in FA subjects when compared to the age match controls. Genotyping of the NOS2 gene c.1823C>T (p. Ser608Leu) (rs2297518), showed statistically significant (P < 0.05) association with FA. Elevated level of 3-NT is one of the cause of NS and NOS2 gene polymorphism associated with FA is an important target in the treatment regimen.


Assuntos
Anemia de Fanconi/genética , Estudos de Associação Genética , Óxido Nítrico Sintase Tipo II/genética , Estresse Nitrosativo/genética , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Adulto , Sequência de Bases , Estudos de Casos e Controles , Criança , Pré-Escolar , Frequência do Gene/genética , Humanos , Óxido Nítrico Sintase Tipo I/genética , Tirosina/análogos & derivados , Tirosina/metabolismo , Adulto Jovem
4.
Blood Cells Mol Dis ; 85: 102465, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32693366

RESUMO

Ploidy, besides known translocations in lymphoblasts, is a strong predictor of prognosis in B- cell progenitor acute lymphoblastic leukemia (BCP-ALL). While hyperdiploidy with >50 chromosomes shows a favourable outcome, hypodiploidy with <45 chromosomes have a dismal clinical outcome. However, there exists a small subset where both the hypodiploid and hyperdiploid clones are apparent either by cytogenetics or flow cytometry and are defined partially masked hypodiploids or mosaics based on the percentage of clonal population. These patients are essentially hypodiploids, and show the hyperdiploid clone as a consequence of endoreduplication of the primary hypodiploid clone- A phenomenon of successive replication of genome without mitosis (cytokinesis) resulting in increased ploidy. In the current study, we present the complete clinical, hematological and cytogenetic profile of 11 such newly diagnosed mosaics or partially masked hypodiploid BCP-ALL cases.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Adolescente , Adulto , Criança , Pré-Escolar , Análise Citogenética , Endorreduplicação , Feminino , Humanos , Masculino , Ploidias , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Prognóstico , Translocação Genética , Adulto Jovem
6.
Blood Cells Mol Dis ; 59: 52-7, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27282568

RESUMO

Myelodysplastic syndromes (MDSs) are heterogeneous clonal haematopoeitic stem cell disorders characterized by ineffective haematopoeisis, cytopenias and risk of progression to AML. We studied 150 MDS patients for cytogenetic aberrations and 60 patients with normal karyotype and 40 patients harboring cytogenetic abnormalities for copy number variations (CNVs). Cytogenetic abnormalities were detected in 46% of patients with a majority of patients harboring abnormalities of chromosome 7 and del (20q) at frequencies of 16% and 12% respectively. We explored the potential of quantitative multiplex PCR assay of short fluorescent fragments (QMPSF) to identify CNVs and correlated the findings with cytogenetic data and disease prognosis. CNVs (n=31) were detected in 28.3% of karyotypically normal and 23% patients with abnormal karyotype. Genetic losses or deletions (n=26) were more frequent than duplications (n=5). EPO (7q22) and SEC-61(7p11) emerged as new candidate genes susceptible to genetic losses with 57.7% deletions identified in regions on chromosome 7. The CNVs correlated with International Prognostic Scoring System (IPSS) intermediate disease risk group. Our integrative cytogenetic and copy number variation study suggests that abnormalities of chromosome 7 are predominant in Indian population and that they may play a secondary role in disease progression and should be evaluated further for asserting their clinical significance and influence on disease prognosis.


Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 7/genética , Variações do Número de Cópias de DNA , Eritropoetina/genética , Canais de Translocação SEC/genética , Deleção de Genes , Humanos , Índia , Síndromes Mielodisplásicas/genética , Prognóstico
7.
Sci Rep ; 12(1): 5925, 2022 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-35396491

RESUMO

Myelodysplastic syndromes (MDS) are a group of clonal hematological disease with high risk of progression to AML. Accurate risk stratification is of importance for the proper management of MDS. Genetic lesions (Cytogenetic and Molecular mutations) are known to help in prognosticating the MDS patients. We have studied 152 MDS patients using cytogenetics and next generation sequencing (NGS). These patients were evaluated and as per cytogenetic prognostic group, majority (92.1%) of the patients classified as good (81.6%) and intermediate (10.5%) group. The NGS identified 38 different gene mutations in our cohort. Among 111 MDS patients with mutations, the most frequent mutated genes were SF3B1 (25.2%), SRSF2 (19%) U2AF1 (14.4%) ASXL1 (9.9%) RUNX1 (9.9%) TET2 (9%), TP53 (9%), ATM (6.3%), NRAS (5.4%) and JAK2/3 (5.4%). The survival analysis revealed that the mutations in TP53, JAK2/3, KRAS, NRAS and ASXL1 were significantly (P < 0.05) associated with poor survival of the patients. The univariate cox and multivariate cox analysis of our study suggested that the age, marrow morphology, cytogenetic and gene mutations with IPSS-R should be considered for prognosticating the MDS patients. We have proposed M-IPSS-R which changed the risk stratification i.e. 66.3% patients had decreased risk whereas 33.75% showed increased risk compared to IPSS-R. The survival analysis also showed that the M-IPSS-R were more significant in separating the patients as per their risk than the IPSS-R alone. The change in risk stratification could help in proper strategy for the treatment planning.


Assuntos
Síndromes Mielodisplásicas , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Prognóstico , Análise de Sobrevida
8.
Cancer Genet ; 256-257: 17-20, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33823403

RESUMO

Acute Myeloid Leukemia (AML) is a heterogeneous disease with respect to morphology, immunophenotype, chromosomal abnormalities and genetic lesions. While a majority of AML cases harbour recurrent chromosomal abnormalities, several rare, apparently unique or novel aberrations may be identified by conventional cytogenetics. In fact, with the prognostic relevance of chromosomal abnormalities, and with the advent of new-age, target-specific therapy, identifying such aberrations becomes vital. In this study, we present a case of pediatric AML with ins(19;X)(q13.1;p11.2q28) and t(1;11)(q10;p10), both, novel, previously unreported chromosomal abnormalities in AML. Post induction, both these clonal cytogenetic abnormalities persisted. The documentation of this case will help determine the significance of these cytogenetic abnormalities. Also, this case exemplifies the importance of cytogenetics in the complete characterization and risk stratification of AML patients.


Assuntos
Inversão Cromossômica , Análise Citogenética , Translocação Genética , Criança , Feminino , Seguimentos , Humanos , Cariótipo
10.
PLoS One ; 11(1): e0147016, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26799702

RESUMO

Fanconi anemia (FA), a rare heterogeneous genetic disorder, is known to be associated with 19 genes and a spectrum of clinical features. We studied FANCA molecular changes in 34 unrelated and 2 siblings of Indian patients with FA and have identified 26 different molecular changes of FANCA gene, of which 8 were novel mutations (a small deletion c.2500delC, 4 non-sense mutations c.2182C>T, c.2630C>G, c.3677C>G, c.3189G>A; and 3 missense mutations; c.1273G>C, c.3679 G>C, and c.3992 T>C). Among these only 16 patients could be assigned FA-A complementation group, because we could not confirm single exon deletions detected by MLPA or cDNA amplification by secondary confirmation method and due to presence of heterozygous non-pathogenic variations or heterozygous pathogenic mutations. An effective molecular screening strategy should be developed for confirmation of these mutations and determining the breakpoints for single exon deletions.


Assuntos
Proteína do Grupo de Complementação A da Anemia de Fanconi/genética , Anemia de Fanconi/genética , Mutação , Sítios Frágeis do Cromossomo , Anemia de Fanconi/patologia , Genótipo , Índia , Fenótipo , Ubiquitinação
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