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1.
Blood ; 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34748628

RESUMO

Idiopathic aplastic anemia (IAA) is a rare autoimmune bone marrow failure disorder initiated by a human leukocyte antigen (HLA)-restricted T cell response to unknown antigens. As for other autoimmune disorders, the predilection for certain HLA profiles seems to represent an etiologic factor, however, the structure-function patterns involved in the self-presentation in this disease remain unclear. Herein we analyzed the molecular landscape of HLA complexes of a cohort of 300 IAA patients and almost 3000 healthy and disease controls, by deeply dissecting their genotypic configurations, functional divergence, self-antigen binding capabilities and T cell receptor (TCR) repertoire specificities. Specifically, analysis of the evolutionary divergence of HLA genotypes (HED) showed that IAA patients carried class II HLA molecules whose antigen binding sites were characterized by a high level of structural homology, only partially explained by specific risk allele profiles. This pattern implies reduced HLA binding capabilities, confirmed by binding analysis of hematopoietic stem cell derived self-peptides. IAA phenotype was associated with the enrichment in a few amino acids at specific positions within the peptide binding groove of DRB1 molecules, affecting the interface HLA-antigen-TCR ß and potentially constituting the basis of T-cell dysfunction and autoreactivity. When analyzing associations with clinical outcomes, low HED was associated with risk of malignant progression and worse survival, underlying reduced tumor surveillance in clearing potential neoantigens derived from mechanisms of clonal hematopoiesis. Our data shed light on the immunogenetic risk associated with IAA etiology and clonal evolution, and on general pathophysiological mechanisms potentially involved also in other autoimmune disorders.

4.
Blood Adv ; 2021 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-34768283

RESUMO

Decrease in DNA dioxygease activity generated by TET2 gene family is crucial in myelodysplastic syndromes (MDS). The general down-regulation of 5-hydroxymethylcytosine (5-hmC) argues for a role of DNA demethylation in MDS beyond TET2 mutations, which albeit frequent, do not convey any prognostic significance. We investigated TETs expression to identify factors which can modulate the impact of mutations and thus 5-hmC levels on clinical phenotypes and prognosis of MDS patients. DNA/RNA-sequencing and 5-hmC data were collected from 1,665 patients with MDS and 91 controls. Irrespective of mutations, a significant fraction of MDS patients exhibited lower TET2 expression, while 5-hmC levels were not uniformly decreased. In searching for factors explaining compensatory mechanisms, we discovered that TET3 was up-regulated in MDS and inversely correlated with TET2 expression in wild-type cases. While TET2 was reduced across all age-groups, TET3 levels were increased in a likely feedback mechanism induced by TET2 dysfunction. This inverse relationship of TET2 and TET3 expression also corresponded to the expression of L-2-hydroxyglutarate dehydrogenase, involved in agonist/antagonist substrate metabolism. Importantly, elevated TET3 levels influenced the clinical phenotype of TET2-deficiency whereby the lack of compensation by TET3 (low TET3 expression) was associated with poor outcomes of TET2 mutant carriers.

9.
Cancers (Basel) ; 13(17)2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34503230

RESUMO

Large Granular Lymphocyte Leukemia (LGLL) is a rare, chronic lymphoproliferative disorder of effector cytotoxic T-cells, and less frequently, natural killer (NK) cells. The disease is characterized by an indolent and often asymptomatic course. However, in roughly 50% of cases, treatment is required due to severe transfusion-dependent anemia, severe neutropenia, or moderate neutropenia with associated recurrent infections. LGLL represents an interesting disease process at the intersection of a physiological immune response, autoimmune disorder, and malignant (clonal) proliferation, resulting from the aberrant activation of cellular pathways promoting survival, proliferation, and evasion of apoptotic signaling. LGLL treatment primarily consists of immunosuppressive agents (methotrexate, cyclosporine, and cyclophosphamide), with a cumulative response rate of about 60% based on longitudinal expertise and retrospective studies. However, refractory cases can result in clinical scenarios characterized by transfusion-dependent anemia and severe neutropenia, which warrant further exploration of other potential targeted treatment modalities. Here, we summarize the current understanding of the immune-genomic profiles of LGLL, its pathogenesis, and current treatment options, and discuss potential novel therapeutic agents, particularly for refractory disease.

11.
Clin Case Rep ; 9(9): e04533, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34552731

RESUMO

We report on a novel, successful, non-cytotoxic therapy to treat multiply-refractory T-LGL in an elderly patient.

13.
Cell Stem Cell ; 28(11): 1966-1981.e6, 2021 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-34473945

RESUMO

DDX41 mutations are the most common germline alterations in adult myelodysplastic syndromes (MDSs). The majority of affected individuals harbor germline monoallelic frameshift DDX41 mutations and subsequently acquire somatic mutations in their other DDX41 allele, typically missense R525H. Hematopoietic progenitor cells (HPCs) with biallelic frameshift and R525H mutations undergo cell cycle arrest and apoptosis, causing bone marrow failure in mice. Mechanistically, DDX41 is essential for small nucleolar RNA (snoRNA) processing, ribosome assembly, and protein synthesis. Although monoallelic DDX41 mutations do not affect hematopoiesis in young mice, a subset of aged mice develops features of MDS. Biallelic mutations in DDX41 are observed at a low frequency in non-dominant hematopoietic stem cell clones in bone marrow (BM) from individuals with MDS. Mice chimeric for monoallelic DDX41 mutant BM cells and a minor population of biallelic mutant BM cells develop hematopoietic defects at a younger age, suggesting that biallelic DDX41 mutant cells are disease modifying in the context of monoallelic DDX41 mutant BM.


Assuntos
RNA Helicases DEAD-box , Síndromes Mielodisplásicas , Animais , RNA Helicases DEAD-box/genética , Células Germinativas , Hematopoese/genética , Camundongos , Mutação/genética , Síndromes Mielodisplásicas/genética
15.
Acta Oncol ; 60(11): 1520-1526, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34461798

RESUMO

BACKGROUND: Acute promyelocytic leukemia (APL) is uncommon among subjects aged ≥ 70 years and the better therapeutic strategy represents an unmet clinical need. MATERIALS AND METHODS: This prompted us to explore our real-life data on a retrospective cohort of 45 older APL patients (≥ 70 years) consecutively diagnosed at eight different hematologic institutions in Latium, Italy, from July 1991 to May 2019. RESULTS: Two patients (4.4%) died from early hemorrhagic complications before treatment could begin. Twenty-two patients (51.1%) (Group A) were enrolled or treated according to standard clinical protocols, while 21 (48.8%) (Group B) received an ATRA-based personalized approach due to poor performance status. Morphologic complete remission (CR) after induction therapy was achieved in 33 patients (76.7%) with 100% of patients in Group A and 52.3% in Group B (p < 0.001). Molecular CR was documented in 30 patients (69.7%) [20/22 (90.9%) in Group A and 10/21 (47.6%) in Group B (p = 0.002)]. Ten patients (23.2%) died during induction therapy, all in Group B. Five-year overall survival (OS) of the entire cohort was 46.1% (95% CI 28.2-64.0), with 72.6% (95% CI 42.9-100) in Group A vs. 27.2% (95% CI 7.5-46.9) in the Group B (p = 0.001). CONCLUSIONS: The present analysis highlights that almost half of the patients received sub-optimal induction treatments and registered dismal outcomes demonstrating the importance of adopting standard therapies instead of modified or reduced personalized approaches also in the setting of frail older patients.


Assuntos
Leucemia Promielocítica Aguda , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Trióxido de Arsênio/uso terapêutico , Humanos , Leucemia Promielocítica Aguda/tratamento farmacológico , Indução de Remissão , Estudos Retrospectivos , Resultado do Tratamento , Tretinoína/uso terapêutico
16.
Cells ; 10(8)2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34440730

RESUMO

Multiple myeloma (MM) is a blood cancer characterized by the accumulation of malignant monoclonal plasma cells in the bone marrow. It develops through a series of premalignant plasma cell dyscrasia stages, most notable of which is the Monoclonal Gammopathy of Undetermined Significance (MGUS). Significant advances have been achieved in uncovering the genomic aberrancies underlying the pathogenesis of MGUS-MM. In this review, we discuss in-depth the genomic evolution of MM and focus on the prognostic implications of the accompanied molecular and cytogenetic aberrations. We also dive into the latest investigatory techniques used for the diagnoses and risk stratification of MM patients.


Assuntos
Expressão Gênica , Mieloma Múltiplo/genética , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Humanos , Gamopatia Monoclonal de Significância Indeterminada/genética , Gamopatia Monoclonal de Significância Indeterminada/patologia , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Polimorfismo de Nucleotídeo Único , Prognóstico , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteínas ras/genética , Proteínas ras/metabolismo
18.
JCI Insight ; 6(13)2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34236054

RESUMO

TCR repertoire diversification constitutes a foundation for successful immune reconstitution after allogeneic hematopoietic cell transplantation (allo-HCT). Deep TCR Vß sequencing of 135 serial specimens from a cohort of 35 allo-HCT recipients/donors was performed to dissect posttransplant TCR architecture and dynamics. Paired analysis of clonotypic repertoires showed a minimal overlap with donor expansions. Rarefied and hyperexpanded clonotypic patterns were hallmarks of T cell reconstitution and influenced clinical outcomes. Donor and pretransplant TCR diversity as well as divergence of class I human leukocyte antigen genotypes were major predictors of recipient TCR repertoire recovery. Complementary determining region 3-based specificity spectrum analysis indicated a predominant expansion of pathogen- and tumor-associated clonotypes in the late post-allo-HCT phase, while autoreactive clones were more expanded in the case of graft-versus-host disease occurrence. These findings shed light on post-allo-HCT adaptive immune reconstitution processes and possibly help in tracking alloreactive responses.

19.
Blood ; 138(19): 1885-1895, 2021 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-34075412

RESUMO

Although genomic alterations drive the pathogenesis of acute myeloid leukemia (AML), traditional classifications are largely based on morphology, and prototypic genetic founder lesions define only a small proportion of AML patients. The historical subdivision of primary/de novo AML and secondary AML has shown to variably correlate with genetic patterns. The combinatorial complexity and heterogeneity of AML genomic architecture may have thus far precluded genomic-based subclassification to identify distinct molecularly defined subtypes more reflective of shared pathogenesis. We integrated cytogenetic and gene sequencing data from a multicenter cohort of 6788 AML patients that were analyzed using standard and machine learning methods to generate a novel AML molecular subclassification with biologic correlates corresponding to underlying pathogenesis. Standard supervised analyses resulted in modest cross-validation accuracy when attempting to use molecular patterns to predict traditional pathomorphologic AML classifications. We performed unsupervised analysis by applying the Bayesian latent class method that identified 4 unique genomic clusters of distinct prognoses. Invariant genomic features driving each cluster were extracted and resulted in 97% cross-validation accuracy when used for genomic subclassification. Subclasses of AML defined by molecular signatures overlapped current pathomorphologic and clinically defined AML subtypes. We internally and externally validated our results and share an open-access molecular classification scheme for AML patients. Although the heterogeneity inherent in the genomic changes across nearly 7000 AML patients was too vast for traditional prediction methods, machine learning methods allowed for the definition of novel genomic AML subclasses, indicating that traditional pathomorphologic definitions may be less reflective of overlapping pathogenesis.

20.
Blood ; 138(15): 1331-1344, 2021 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-33971010

RESUMO

The mechanism underlying cell type-specific gene induction conferred by ubiquitous transcription factors as well as disruptions caused by their chimeric derivatives in leukemia is not well understood. Here, we investigate whether RNAs coordinate with transcription factors to drive myeloid gene transcription. In an integrated genome-wide approach surveying for gene loci exhibiting concurrent RNA and DNA interactions with the broadly expressed Runt-related transcription factor 1 (RUNX1), we identified the long noncoding RNA (lncRNA) originating from the upstream regulatory element of PU.1 (LOUP). This myeloid-specific and polyadenylated lncRNA induces myeloid differentiation and inhibits cell growth, acting as a transcriptional inducer of the myeloid master regulator PU.1. Mechanistically, LOUP recruits RUNX1 to both the PU.1 enhancer and the promoter, leading to the formation of an active chromatin loop. In t(8;21) acute myeloid leukemia (AML), wherein RUNX1 is fused to ETO, the resulting oncogenic fusion protein, RUNX1-ETO, limits chromatin accessibility at the LOUP locus, causing inhibition of LOUP and PU.1 expression. These findings highlight the important role of the interplay between cell-type-specific RNAs and transcription factors, as well as their oncogenic derivatives in modulating lineage-gene activation and raise the possibility that RNA regulators of transcription factors represent alternative targets for therapeutic development.

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