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Artigo em Inglês | MEDLINE | ID: mdl-31677197


T-cell prolymphocytic leukemia (T-PLL) is an aggressive tumor with leukemic presentation of mature T-lymphocytes. Here, we aimed at characterizing the initial events in the molecular pathogenesis of T-PLL and particularly, at determining the point in T-cell differentiation when the hallmark oncogenic events, that is, inv(14)(q11q32)/t(14;14)(q11;q32) and t(X;14)(q28;q11) occur. To this end, we mined whole genome and transcriptome sequencing data of 17 and 11 T-PLL cases, respectively. Mapping of the 14q32.1 locus breakpoints identified only TCL1A, which was moreover significantly overexpressed in T-PLL as compared to benign CD4+ and CD8+ T-cells, as the only common oncogenic target of aberrations. In cases with t(14;14), the breakpoints mapped telomeric and in cases with inv(14) centromeric or in the 3'-untranslated region of TCL1A. Regarding the T-cell receptor alpha (TRA) locus-TCL1A breakpoint junctions, all 17 breakpoints involved recombination signal sequences and 15 junctions contained nontemplated (N-) nucleotides. All T-PLL cases studied carried in-frame TRA rearrangements on the intact allele, which skewed significantly toward usage of distal/central TRAV/TRAJ gene segments as compared to the illegitimate TRA rearrangements. Our findings suggest that the oncogenic TRA-TCL1A/MTCP1 rearrangements in T-PLL occur during opening of the TRA locus, that is, during the progression from CD4+ immature single positive to early double positive thymocyte stage, just before physiologic TCL1A expression is silenced. The cell carrying such an oncogenic event continues maturation and rearranges the second TRA allele to achieve a functional T-cell receptor. Thereafter, it switches off RAG and DNTT expression in line with the mature T-cell phenotype at presentation of T-PLL.

Haematologica ; 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31467127


To identify genomic alterations contributing to the pathogenesis of high risk chronic lymphocytic leukemia beyond the well established role of TP53 aberrations, we comprehensively analyzed 75 relapsed/refractory and 71 treatment naive high risk cases from prospective clinical trials by single nucleotide polymorphism arrays and targeted next generation sequencing. Increased genomic complexity was a hallmark of relapsed/refractory and treatment naive high risk chronic lymphocytic leukemia. In relapsed/refractory cases previously exposed to the selective pressure of chemo(immuno)therapy, gain(8)(q24.21) and del(9)(p21.3) were found particularly enriched. Both alterations affected key regulators of cell cycle progression, namely MYC and CDKN2A/B. While homozygous CDKN2A/B loss has been directly associated with Richter transformation, we did not find this association for heterozygous loss of CDKN2A/B. Gains in 8q24.21 were either focal gains in a MYC enhancer region or large gains affecting the MYC locus, but only the latter type was highly enriched in relapsed/refractory chronic lymphocytic leukemia (17%). In addition to a high frequency of NOTCH1 mutations (23%), we found recurrent genetic alterations in SPEN (4% mutated), RBPJ (8% deleted) and SNW1 (8% deleted), all affecting a protein complex that represses transcription of NOTCH1 target genes. We investigated the functional impact of these alterations on HES1, DTX1 and MYC gene transcription and found de repression of these NOTCH1 target genes particularly with SPEN mutations. In summary, we provide new insights into the genomic architecture of high risk chronic lymphocytic leukemia, define novel recurrent DNA copy number alterations and refine knowledge on del(9p), gain(8q) and alterations affecting NOTCH1 signaling. The study was registered at with number NCT01392079.

Leukemia ; 33(6): 1427-1438, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30573773


Targeting B-cell receptor signaling using the PI3Kδ inhibitor idelalisib is a highly effective treatment option for relapsed/refractory chronic lymphocytic leukemia (CLL) patients. In addition to its direct impact on tumor cells, PI3Kδ inhibition can modulate the activity of regulatory T-cells (Tregs) resulting in enhanced anti-tumoral immune functions which may contribute to the success of PI3Kδ inhibitors in cancer therapy. The role of Tregs in CLL and their modulation by PI3Kδ inhibitors was so far poorly understood. Using the Eµ-TCL1 adoptive transfer model of CLL, we show that disease development induces the accumulation of activated and highly immunosuppressive Tregs. Depletion of CD25+ Tregs using anti-CD25 antibodies resulted in enhanced CD8+ T-cell activation, effector differentiation, and functional capacity. We further show that pharmacological inhibition of PI3Kδ effectively controlled disease and significantly decreased both CD25+ and CD25- Treg numbers, proliferation and activation status in CLL-bearing mice. Nonetheless, this PI3Kδ-mediated decrease in Tregs did not translate into better CD8+ T-cell function, as PI3Kδ inhibition concomitantly abrogated T-cell receptor signaling in CD8+ T-cells leading to decreased activation, effector cell differentiation and proliferation. Collectively, these data highlight the strong immunomodulatory effects of PI3Kδ inhibitors in CLL and are of relevance for a rational design of idelalisib-based combination therapies in CLL.

Antineoplásicos/farmacologia , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/efeitos dos fármacos , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Leucemia Linfocítica Crônica de Células B/imunologia , Purinas/farmacologia , Quinazolinonas/farmacologia , Linfócitos T Reguladores/imunologia , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais , Linfócitos T Reguladores/efeitos dos fármacos , Células Tumorais Cultivadas