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1.
Nature ; 632(8027): 1082-1091, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39143224

RESUMO

T-lineage acute lymphoblastic leukaemia (T-ALL) is a high-risk tumour1 that has eluded comprehensive genomic characterization, which is partly due to the high frequency of noncoding genomic alterations that result in oncogene deregulation2,3. Here we report an integrated analysis of genome and transcriptome sequencing of tumour and remission samples from more than 1,300 uniformly treated children with T-ALL, coupled with epigenomic and single-cell analyses of malignant and normal T cell precursors. This approach identified 15 subtypes with distinct genomic drivers, gene expression patterns, developmental states and outcomes. Analyses of chromatin topology revealed multiple mechanisms of enhancer deregulation that involve enhancers and genes in a subtype-specific manner, thereby demonstrating widespread involvement of the noncoding genome. We show that the immunophenotypically described, high-risk entity of early T cell precursor ALL is superseded by a broader category of 'early T cell precursor-like' leukaemia. This category has a variable immunophenotype and diverse genomic alterations of a core set of genes that encode regulators of hematopoietic stem cell development. Using multivariable outcome models, we show that genetic subtypes, driver and concomitant genetic alterations independently predict treatment failure and survival. These findings provide a roadmap for the classification, risk stratification and mechanistic understanding of this disease.


Assuntos
Genoma Humano , Genômica , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Criança , Feminino , Humanos , Masculino , Cromatina/genética , Cromatina/metabolismo , Elementos Facilitadores Genéticos/genética , Epigenômica , Regulação Leucêmica da Expressão Gênica , Genoma Humano/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Análise de Célula Única , Transcriptoma/genética , Linfócitos T/citologia , Linfócitos T/patologia
2.
Genes Chromosomes Cancer ; 63(4): e23235, 2024 04.
Artigo em Inglês | MEDLINE | ID: mdl-38656651

RESUMO

In myeloid neoplasms, both fusion genes and gene mutations are well-established events identifying clinicopathological entities. In this study, we present a thus far undescribed t(X;21)(p11.4;q22.12) in five cases with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). The translocation was isolated or accompanied by additional changes. It did not generate any fusion gene or gene deregulation by aberrant juxtaposition with regulatory sequences. Molecular analysis by targeted next-generation sequencing showed that the translocation was accompanied by at least one somatic mutation in TET2, EZH2, RUNX1, ASXL1, SRSF2, ZRSR2, DNMT3A, and NRAS genes. Co-occurrence of deletion of RUNX1 in 21q22 and of BCOR in Xp11 was associated with t(X;21). BCOR haploinsufficiency corresponded to a significant hypo-expression in t(X;21) cases, compared to normal controls and to normal karyotype AML. By contrast, RUNX1 expression was not altered, suggesting a compensatory effect by the remaining allele. Whole transcriptome analysis showed that overexpression of HOXA9 differentiated t(X;21) from both controls and t(8;21)-positive AML. In conclusion, we characterized a new recurrent reciprocal t(X;21)(p11.4;q22.12) chromosome translocation in MDS and AML, generating simultaneous BCOR and RUNX1 deletions rather than a fusion gene at the genomic level.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core , Síndromes Mielodisplásicas , Proteínas Proto-Oncogênicas , Proteínas Repressoras , Translocação Genética , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cromossomos Humanos Par 21/genética , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Mutação , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética
3.
Blood ; 138(9): 773-784, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-33876209

RESUMO

Acute leukemias (ALs) of ambiguous lineage are a heterogeneous group of high-risk leukemias characterized by coexpression of myeloid and lymphoid markers. In this study, we identified a distinct subgroup of immature acute leukemias characterized by a broadly variable phenotype, covering acute myeloid leukemia (AML, M0 or M1), T/myeloid mixed-phenotype acute leukemia (T/M MPAL), and early T-cell precursor acute lymphoblastic leukemia (ETP-ALL). Rearrangements at 14q32/BCL11B are the cytogenetic hallmark of this entity. In our screening of 915 hematological malignancies, there were 202 AML and 333 T-cell acute lymphoblastic leukemias (T-ALL: 58, ETP; 178, non-ETP; 8, T/M MPAL; 89, not otherwise specified). We identified 20 cases of immature leukemias (4% of AML and 3.6% of T-ALL), harboring 4 types of 14q32/BCL11B translocations: t(2,14)(q22.3;q32) (n = 7), t(6;14)(q25.3;q32) (n = 9), t(7;14)(q21.2;q32) (n = 2), and t(8;14)(q24.2;q32) (n = 2). The t(2;14) produced a ZEB2-BCL11B fusion transcript, whereas the other 3 rearrangements displaced transcriptionally active enhancer sequences close to BCL11B without producing fusion genes. All translocations resulted in the activation of BCL11B, a regulator of T-cell differentiation associated with transcriptional corepressor complexes in mammalian cells. The expression of BCL11B behaved as a disease biomarker that was present at diagnosis, but not in remission. Deregulation of BCL11B co-occurred with variants at FLT3 and at epigenetic modulators, most frequently the DNMT3A, TET2, and/or WT1 genes. Transcriptome analysis identified a specific expression signature, with significant downregulation of BCL11B targets, and clearly separating BCL11B AL from AML, T-ALL, and ETP-ALL. Remarkably, an ex vivo drug-sensitivity profile identified a panel of compounds with effective antileukemic activity.


Assuntos
Biomarcadores Tumorais , Cromossomos Humanos Par 14/genética , Regulação Leucêmica da Expressão Gênica , Leucemia Mieloide Aguda , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Proteínas Repressoras , Translocação Genética , Proteínas Supressoras de Tumor , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Criança , Pré-Escolar , Feminino , Perfilação da Expressão Gênica , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Proteínas Repressoras/biossíntese , Proteínas Repressoras/genética , Proteínas Supressoras de Tumor/biossíntese , Proteínas Supressoras de Tumor/genética
4.
Ann Hematol ; 101(2): 297-307, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34859285

RESUMO

Platelet-derived growth factor receptor B (PDGFRB) gene rearrangements define a unique subgroup of myeloid and lymphoid neoplasms frequently associated with eosinophilia and characterized by high sensitivity to tyrosine kinase inhibition. To date, various PDGFRB/5q32 rearrangements, involving at least 40 fusion partners, have been reported. However, information on genomic and clinical features accompanying rearrangements of PDGFRB is still scarce. Here, we characterized a series of 14 cases with a myeloid neoplasm using cytogenetic, single nucleotide polymorphism array, and next-generation sequencing. We identified nine PDGFRB translocation partners, including the KAZN gene at 1p36.21 as a novel partner in a previously undescribed t(1;5)(p36;q33) chromosome change. In all cases, the PDGFRB recombination was the sole cytogenetic abnormality underlying the phenotype. Acquired somatic variants were mainly found in clinically aggressive diseases and involved epigenetic genes (TET2, DNMT3A, ASXL1), transcription factors (RUNX1 and CEBPA), and signaling modulators (HRAS). By using both cytogenetic and nested PCR monitoring to evaluate response to imatinib, we found that, in non-AML cases, a low dosage (100-200 mg) is sufficient to induce and maintain longstanding hematological, cytogenetic, and molecular remissions.


Assuntos
Rearranjo Gênico , Leucemia Mieloide/genética , Doenças Mieloproliferativas-Mielodisplásicas/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Adulto , Idoso , Aberrações Cromossômicas , Proteínas do Citoesqueleto/genética , Eosinofilia/genética , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas de Fusão Oncogênica/genética , Polimorfismo de Nucleotídeo Único , Translocação Genética , Adulto Jovem
5.
Genes Chromosomes Cancer ; 60(7): 482-488, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33611795

RESUMO

We investigated MYB rearrangements (MYB-R) and the levels of MYB expression, in 331 pediatric and adult patients with T-cell acute lymphoblastic leukemia (T-ALL). MYB-R were detected in 17 cases and consisted of MYB tandem duplication (tdup) (= 14) or T cell receptor beta locus (TRB)-MYB (= 3). As previously reported, TRB-MYB was found only in children (1.6%) while MYB tdup occurred in both age groups, although it was slightly more frequent in children (5.2% vs 2.8%). Shared features of MYB-R T-ALL were a non-early T-cell precursor (ETP) phenotype, a high incidence of NOTCH1/FBXW7 mutations (81%) and CDKN2AB deletions (70.5%). Moreover, they mainly belonged to HOXA (=8), NKX2-1/2-2/TLX1 (=4), and TLX3 (=3) homeobox-related subgroups. Overall, MYB-R cases had significantly higher levels of MYB expression than MYB wild type (MYB-wt) cases, although high levels of MYB were detected in ~ 30% of MYB-wt T-ALL. Consistent with the transcriptional regulatory networks, cases with high MYB expression were significantly enriched within the TAL/LMO subgroup (P = .017). Interestingly, analysis of paired diagnosis/remission samples demonstrated that a high MYB expression was restricted to the leukemic clone. Our study has indicated that different mechanisms underlie MYB deregulation in 30%-40% of T-ALL and highlighted that, MYB has potential as predictive/prognostic marker and/or target for tailored therapy.


Assuntos
Biomarcadores Tumorais/genética , Duplicação Gênica , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Proteínas Proto-Oncogênicas c-myb/genética , Adolescente , Biomarcadores Tumorais/metabolismo , Criança , Pré-Escolar , Regulação para Baixo , Proteína 7 com Repetições F-Box-WD/genética , Feminino , Proteína Homeobox Nkx-2.2/genética , Proteínas de Homeodomínio/genética , Humanos , Lactente , Masculino , Mutação , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Proteínas Proto-Oncogênicas c-myb/metabolismo , Receptor Notch1/genética , Fator Nuclear 1 de Tireoide/genética
6.
Haematologica ; 101(8): 951-8, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27151989

RESUMO

Recurrent deletions of the long arm of chromosome 5 were detected in 23/200 cases of T-cell acute lymphoblastic leukemia. Genomic studies identified two types of deletions: interstitial and terminal. Interstitial 5q deletions, found in five cases, were present in both adults and children with a female predominance (chi-square, P=0.012). Interestingly, these cases resembled immature/early T-cell precursor acute lymphoblastic leukemia showing significant down-regulation of five out of the ten top differentially expressed genes in this leukemia group, including TCF7 which maps within the 5q31 common deleted region. Mutations of genes known to be associated with immature/early T-cell precursor acute lymphoblastic leukemia, i.e. WT1, ETV6, JAK1, JAK3, and RUNX1, were present, while CDKN2A/B deletions/mutations were never detected. All patients had relapsed/resistant disease and blasts showed an early differentiation arrest with expression of myeloid markers. Terminal 5q deletions, found in 18 of patients, were more prevalent in adults (chi-square, P=0.010) and defined a subgroup of HOXA-positive T-cell acute lymphoblastic leukemia characterized by 130 up- and 197 down-regulated genes. Down-regulated genes included TRIM41, ZFP62, MAPK9, MGAT1, and CNOT6, all mapping within the 1.4 Mb common deleted region at 5q35.3. Of interest, besides CNOT6 down-regulation, these cases also showed low BTG1 expression and a high incidence of CNOT3 mutations, suggesting that the CCR4-NOT complex plays a crucial role in the pathogenesis of HOXA-positive T-cell acute lymphoblastic leukemia with terminal 5q deletions. In conclusion, interstitial and terminal 5q deletions are recurrent genomic losses identifying distinct subtypes of T-cell acute lymphoblastic leukemia.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 5 , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Adolescente , Adulto , Biomarcadores , Criança , Estudos de Coortes , Feminino , Perfilação da Expressão Gênica , Estudos de Associação Genética , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Fenótipo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Adulto Jovem
7.
Blood ; 121(25): 5064-7, 2013 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-23673860

RESUMO

The MLLT10 gene, located at 10p13, is a known partner of MLL and PICALM in specific leukemic fusions generated from recurrent 11q23 and 11q14 chromosome translocations. Deep sequencing recently identified NAP1L1/12q21 as another MLLT10 partner in T-cell acute lymphoblastic leukemia (T-ALL). In pediatric T-ALL, we have identified 2 RNA processing genes, that is, HNRNPH1/5q35 and DDX3X/Xp11.3 as new MLLT10 fusion partners. Gene expression profile signatures of the HNRNPH1- and DDX3X-MLLT10 fusions placed them in the HOXA subgroup. Remarkably, they were highly similar only to PICALM-MLLT10-positive cases. The present study showed MLLT10 promiscuity in pediatric T-ALL and identified a specific MLLT10 signature within the HOXA subgroup.


Assuntos
RNA Helicases DEAD-box/genética , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Fatores de Transcrição/genética , Criança , Humanos , Hibridização in Situ Fluorescente , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcriptoma , Translocação Genética
8.
Leukemia ; 36(11): 2577-2585, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35974102

RESUMO

Chromothripsis is a mitotic catastrophe that arises from multiple double strand breaks and incorrect re-joining of one or a few chromosomes. We report on incidence, distribution, and features of chromothriptic events in T-cell acute lymphoblastic leukemias (T-ALL). SNP array was performed in 103 T-ALL (39 ETP/near ETP, 59 non-ETP, and 5 with unknown stage of differentiation), including 38 children and 65 adults. Chromothripsis was detected in 11.6% of all T-ALL and occurred only in adult cases with an immature phenotype (12/39 cases; 30%). It affected 1 to 4 chromosomes, and recurrently involved chromosomes 1, 6, 7, and 17. Abnormalities of genes typically associated with T-ALL were found at breakpoints of chromothripsis. In addition, it gave rise to new/rare alterations, such as, the SFPQ::ZFP36L2 fusion, reported in pediatric T-ALL, deletions of putative suppressors, such as IKZF2 and CSMD1, and amplification of the BCL2 gene. Compared to negative cases, chromothripsis positive T-ALL had a significantly higher level of MYCN expression, and a significant downregulation of RGCC, which is typically induced by TP53 in response to DNA damage. Furthermore we identified mutations and/or deletions of DNA repair/genome stability genes in all cases, and an association with NUP214 rearrangements in 33% of cases.


Assuntos
Cromotripsia , Células Precursoras de Linfócitos T , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Humanos , Rearranjo Gênico , Mutação , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Adulto
9.
Cancer Discov ; 12(4): 1152-1169, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-34903620

RESUMO

NUP98 fusion oncoproteins (FO) are drivers in pediatric leukemias and many transform hematopoietic cells. Most NUP98 FOs harbor an intrinsically disordered region from NUP98 that is prone to liquid-liquid phase separation (LLPS) in vitro. A predominant class of NUP98 FOs, including NUP98-HOXA9 (NHA9), retains a DNA-binding homeodomain, whereas others harbor other types of DNA- or chromatin-binding domains. NUP98 FOs have long been known to form puncta, but long-standing questions are how nuclear puncta form and how they drive leukemogenesis. Here we studied NHA9 condensates and show that homotypic interactions and different types of heterotypic interactions are required to form nuclear puncta, which are associated with aberrant transcriptional activity and transformation of hematopoietic stem and progenitor cells. We also show that three additional leukemia-associated NUP98 FOs (NUP98-PRRX1, NUP98-KDM5A, and NUP98-LNP1) form nuclear puncta and transform hematopoietic cells. These findings indicate that LLPS is critical for leukemogenesis by NUP98 FOs. SIGNIFICANCE: We show that homotypic and heterotypic mechanisms of LLPS control NUP98-HOXA9 puncta formation, modulating transcriptional activity and transforming hematopoietic cells. Importantly, these mechanisms are generalizable to other NUP98 FOs that share similar domain structures. These findings address long-standing questions on how nuclear puncta form and their link to leukemogenesis. This article is highlighted in the In This Issue feature, p. 873.


Assuntos
Leucemia , Complexo de Proteínas Formadoras de Poros Nucleares , Carcinogênese , Núcleo Celular , Criança , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Leucemia/genética , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Proteína 2 de Ligação ao Retinoblastoma
10.
Cereb Cortex ; 20(8): 1915-25, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20016002

RESUMO

Expressed throughout the central nervous system, the myocardin-related, megakaryoblastic acute leukemia 1 and 2 (Mkl1/2) are transcriptional cofactors that can be found tethered in the cytoplasm to monomeric actin but on synaptic activation translocate to the nucleus and associate with transcription factors such as serum response factor (SRF) to regulate expression of structural genes. This implies a potential role for Mkls in linking synaptic activity, through gene-expression control, to neuronal structural plasticity. Here, we present evidence that Mkls, particularly Mkl2, are powerful regulators of neuronal structure in vitro. Moreover, using the passive avoidance-conditioning paradigm, we identify learning-associated alterations of neuronal Mkl expression that appear to contribute to 2 phases of gene regulation during memory consolidation in the hippocampus. Gene regulation immediately after learning includes Egr2 and may be facilitated by downregulation of Mkls likely releasing ternary complex factor-regulated SRF activity. The second transcriptional phase occurs later at the 3-h postavoidance time point when Mkl accumulates in the nucleus of hippocampal neurons and there is enhanced transcription of Mkl-dependent structural genes that may contribute to the elaboration of new, memory-associated synapses known to appear over the subsequent 3-h period.


Assuntos
Hipocampo/metabolismo , Cinesinas/fisiologia , Plasticidade Neuronal/fisiologia , Neurônios/metabolismo , Fatores de Transcrição/fisiologia , Animais , Aprendizagem da Esquiva/fisiologia , Diferenciação Celular/fisiologia , Proteína 2 de Resposta de Crescimento Precoce/genética , Proteína 2 de Resposta de Crescimento Precoce/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Hipocampo/citologia , Masculino , Memória/fisiologia , Plasticidade Neuronal/genética , Neurônios/citologia , Transporte Proteico/genética , Ratos , Ratos Wistar , Transmissão Sináptica/genética , Fatores de Transcrição/genética
11.
Genes (Basel) ; 12(8)2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34440292

RESUMO

T-cell acute lymphoblastic leukemias (T-ALL) are immature lymphoid tumors localizing in the bone marrow, mediastinum, central nervous system, and lymphoid organs. They account for 10-15% of pediatric and about 25% of adult acute lymphoblastic leukemia (ALL) cases. It is a widely heterogeneous disease that is caused by the co-occurrence of multiple genetic abnormalities, which are acquired over time, and once accumulated, lead to full-blown leukemia. Recurrently affected genes deregulate pivotal cell processes, such as cycling (CDKN1B, RB1, TP53), signaling transduction (RAS pathway, IL7R/JAK/STAT, PI3K/AKT), epigenetics (PRC2 members, PHF6), and protein translation (RPL10, CNOT3). A remarkable role is played by NOTCH1 and CDKN2A, as they are altered in more than half of the cases. The activation of the NOTCH1 signaling affects thymocyte specification and development, while CDKN2A haploinsufficiency/inactivation, promotes cell cycle progression. Among recurrently involved oncogenes, a major role is exerted by T-cell-specific transcription factors, whose deregulated expression interferes with normal thymocyte development and causes a stage-specific differentiation arrest. Hence, TAL and/or LMO deregulation is typical of T-ALL with a mature phenotype (sCD3 positive) that of TLX1, NKX2-1, or TLX3, of cortical T-ALL (CD1a positive); HOXA and MEF2C are instead over-expressed in subsets of Early T-cell Precursor (ETP; immature phenotype) and early T-ALL. Among immature T-ALL, genomic alterations, that cause BCL11B transcriptional deregulation, identify a specific genetic subgroup. Although comprehensive cytogenetic and molecular studies have shed light on the genetic background of T-ALL, biomarkers are not currently adopted in the diagnostic workup of T-ALL, and only a limited number of studies have assessed their clinical implications. In this review, we will focus on recurrent T-ALL abnormalities that define specific leukemogenic pathways and on oncogenes/oncosuppressors that can serve as diagnostic biomarkers. Moreover, we will discuss how the complex genomic profile of T-ALL can be used to address and test innovative/targeted therapeutic options.


Assuntos
Biomarcadores Tumorais/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Humanos , Lactente , Oncogenes , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Transcriptoma
13.
J Mol Diagn ; 22(5): 629-639, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32142900

RESUMO

T-cell acute lymphoblastic leukemia (T-ALL) results from deregulation of a number of genes via multiple genomic mechanisms. We designed a comprehensive fluorescence in situ hybridization (CI-FISH) assay that consists of genomic probes to simultaneously investigate oncogenes and oncosuppressors recurrently involved in chromosome rearrangements in T-ALL, which was applied to 338 T-ALL cases. CI-FISH provided genetic classification into one of the well-defined genetic subgroups (ie, TAL/LMO, HOXA, TLX3, TLX1, NKX2-1/2-2, or MEF2C) in 80% of cases. Two patients with translocations of the LMO3 transcription factor were identified, suggesting that LMO3 activation may serve as an alternative to LMO1/LMO2 activation in the pathogenesis of this disease. Moreover, intrachromosomal rearrangements that involved the 10q24 locus were found as a new mechanism of TLX1 activation. An unequal distribution of cooperating genetic defects was found among the six genetic subgroups. Interestingly, deletions that targeted TCF7 or TP53 were exclusively found in HOXA T-ALL, LEF1 defects were prevalent in NKX2-1 rearranged patients, CASP8AP2 and PTEN alterations were significantly enriched in TAL/LMO leukemias, and PTPN2 and NUP214-ABL1 abnormalities occurred in TLX1/TLX3. This work convincingly shows that CI-FISH is a powerful tool to define genetic heterogeneity of T-ALL, which may be applied as a rapid and accurate diagnostic test.


Assuntos
Biomarcadores Tumorais , Hibridização in Situ Fluorescente/métodos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Evolução Clonal/genética , Feminino , Rearranjo Gênico , Heterogeneidade Genética , Testes Genéticos , Estudo de Associação Genômica Ampla , Humanos , Hibridização in Situ Fluorescente/normas , Masculino , Pessoa de Meia-Idade , Translocação Genética , Adulto Jovem
15.
Leukemia ; 33(10): 2481-2494, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30923319

RESUMO

The unbalanced translocation dic(1;7)(q10;p10) in myelodysplastic syndromes (MDS) is originated by centromeric juxtaposition resulting into 1q trisomy and 7q monosomy. More than half of cases arise after chemo/radio-therapy. To date, given the absence of genes within the centromeric regions, no specific molecular events have been identified in this cytogenetic subgroup. We performed the first comprehensive genetic and epigenetic analysis of MDS with dic(1;7)(q10;p10) compared to normal controls and therapy-related myeloid neoplasms (t-MNs). RNA-seq showed a unique downregulated signature in dic(1;7) cases, affecting more than 80% of differentially expressed genes. As revealed by pathway and gene ontology analyses, downregulation of ATP-binding cassette (ABC) transporters and lipid-related genes and upregulation of p53 signaling were the most relevant biological features of dic(1;7). Epigenetic supervised analysis revealed hypermethylation at intronic enhancers in the dicentric subgroup, in which low expression levels of enhancer putative target genes accounted for around 35% of the downregulated signature. Enrichment of Krüppel-like transcription factor binding sites emerged at enhancers. Furthermore, a specific hypermethylated pattern on 1q was found to underlie the hypo-expression of more than 50% of 1q-deregulated genes, despite trisomy. In summary, dic(1;7) in MDS establishes a specific transcriptional program driven by a unique epigenomic signature.


Assuntos
Epigênese Genética/genética , Síndromes Mielodisplásicas/genética , Translocação Genética/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Sítios de Ligação/genética , Transtornos Cromossômicos/genética , Regulação para Baixo/genética , Epigenômica/métodos , Feminino , Humanos , Cariotipagem/métodos , Masculino , Pessoa de Meia-Idade , Monossomia/genética , Estudos Retrospectivos , Transcrição Gênica/genética , Trissomia/genética
16.
Eur J Hum Genet ; 24(10): 1388-95, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27071718

RESUMO

Nuclear pore complexes (NPCs) are large channels spanning the nuclear envelope that mediate nucleocytoplasmic transport. They are composed of multiple copies of ~30 proteins termed nucleoporins (NUPs). Alterations in NUP genes are linked to several human neoplastic and non-neoplastic diseases. This review focuses on NUPs, their genes, localization, function in the NPC and involvement in human diseases.


Assuntos
Doenças Cardiovasculares/metabolismo , Doenças do Sistema Imunitário/metabolismo , Neoplasias/metabolismo , Doenças do Sistema Nervoso/metabolismo , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Animais , Doenças Cardiovasculares/genética , Humanos , Doenças do Sistema Imunitário/genética , Neoplasias/genética , Doenças do Sistema Nervoso/genética , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo
17.
Mol Cytogenet ; 9(1): 68, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27594918

RESUMO

BACKGROUND: Although Philadelphia-negative myeloproliferative neoplasms (Ph-MPN) are usually not aggressive, the type and the number of molecular lesions impact greatly on leukemic transformation. Indeed, the molecular background underlying progression is still largely unexplored even though ASXL1, IDH1/2, SRSF2, and TP53 mutations, together with adverse karyotypic changes, place the patient at high risk of leukemic transformation. CASE PRESENTATION: Our patient, a 64-year old man with a diagnosis of JAK2 (V617F) primary myelofibrosis (PMF) had an unusually rapid leukemic transformation. Genomic profiling showed that TET2 and SRSF2 mutations were also present. At leukemic transformation, the patient developed a complex chromosome rearrangement producing a EWSR1-MYB fusion. Remarkably, the expression of MYB and of its target BCL2 was, respectively, ≥4.7 and ≥2.8 fold higher at leukemic transformation than after chemotherapy, when the patient obtained the hematological remission. At this time point, the EWSR1-MYB fusion disappeared while JAK2 (V617F), TET2, and SRSF2 mutations, as well as PMF morphological features persisted. CONCLUSIONS: Rapid leukemic transformation of JAK2 (V617F) PMF was closely linked to a previously undescribed putative EWSR1-MYB transcription factor which was detected only at disease evolution. We hypothesize that the EWSR1-MYB contributed to leukemia transformation through at least two mechanisms: 1) it sustained MYB expression, and consequently deregulated its target BCL2, a putative onco-suppressor gene; and 2) ectopic EWSR1-MYB expression probably fulfilled its own oncogenic potential as demonstrated for other MYB-fusions. As our study confirmed that MYB is recurrently involved in chronic as well as leukemic transformation of PMF, it appears to be a valid molecular marker for tailored treatments.

18.
PLoS One ; 11(3): e0152321, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27031510

RESUMO

Chromosomal translocations involving the nucleoporin NUP98 have been described in several hematopoietic malignancies, in particular acute myeloid leukemia (AML). In the resulting chimeric proteins, Nup98's N-terminal region is fused to the C-terminal region of about 30 different partners, including homeodomain (HD) transcription factors. While transcriptional targets of distinct Nup98 chimeras related to immortalization are relatively well described, little is known about other potential cellular effects of these fusion proteins. By comparing the sub-nuclear localization of a large number of Nup98 fusions with HD and non-HD partners throughout the cell cycle we found that while all Nup98 chimeras were nuclear during interphase, only Nup98-HD fusion proteins exhibited a characteristic speckled appearance. During mitosis, only Nup98-HD fusions were concentrated on chromosomes. Despite the difference in localization, all tested Nup98 chimera provoked morphological alterations in the nuclear envelope (NE), in particular affecting the nuclear lamina and the lamina-associated polypeptide 2α (LAP2α). Importantly, such aberrations were not only observed in transiently transfected HeLa cells but also in mouse bone marrow cells immortalized by Nup98 fusions and in cells derived from leukemia patients harboring Nup98 fusions. Our findings unravel Nup98 fusion-associated NE alterations that may contribute to leukemogenesis.


Assuntos
Membrana Nuclear/genética , Membrana Nuclear/patologia , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Proteínas de Fusão Oncogênica/genética , Animais , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Ciclo Celular , Proteínas de Ligação a DNA/análise , Proteínas de Ligação a DNA/metabolismo , Células HeLa , Proteínas de Homeodomínio/análise , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Proteínas de Membrana/análise , Proteínas de Membrana/metabolismo , Camundongos , Mitose , Membrana Nuclear/metabolismo , Complexo de Proteínas Formadoras de Poros Nucleares/análise , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Proteínas de Fusão Oncogênica/análise , Proteínas de Fusão Oncogênica/metabolismo , Fenótipo , Translocação Genética
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