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1.
Haematologica ; 108(8): 2044-2058, 2023 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-36815378

RESUMO

NUP98 fusions comprise a family of rare recurrent alterations in AML, associated with adverse outcomes. In order to define the underlying biology and clinical implications of this family of fusions, we performed comprehensive transcriptome, epigenome, and immunophenotypic profiling of 2,235 children and young adults with AML and identified 160 NUP98 rearrangements (7.2%), including 108 NUP98-NSD1 (4.8%), 32 NUP98-KDM5A (1.4%) and 20 NUP98-X cases (0.9%) with 13 different fusion partners. Fusion partners defined disease characteristics and biology; patients with NUP98-NSD1 or NUP98-KDM5A had distinct immunophenotypic, transcriptomic, and epigenomic profiles. Unlike the two most prevalent NUP98 fusions, NUP98-X variants are typically not cryptic. Furthermore, NUP98-X cases are associated with WT1 mutations, and have epigenomic profiles that resemble either NUP98-NSD1 or NUP98-KDM5A. Cooperating FLT3-ITD and WT1 mutations define NUP98-NSD1, and chromosome 13 aberrations are highly enriched in NUP98-KDM5A. Importantly, we demonstrate that NUP98 fusions portend dismal overall survival, with the noteworthy exception of patients bearing abnormal chromosome 13 (clinicaltrials gov. Identifiers: NCT00002798, NCT00070174, NCT00372593, NCT01371981).


Assuntos
Leucemia Mieloide Aguda , Criança , Adulto Jovem , Humanos , Leucemia Mieloide Aguda/genética , Mutação , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Perfilação da Expressão Gênica , Proteína 2 de Ligação ao Retinoblastoma/genética
3.
Pediatr Blood Cancer ; 64(3)2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27667142

RESUMO

Transient myeloproliferative disorder (TMD) is a leukemia type that occurs typically in newborns. In Down syndrome, TMD is referred to as transient abnormal myelopoiesis (TAM).32 Recently, transientness has also been reported in acute myeloid leukemia patients with germline trisomy 21 mosaicism, and even in cases with somatic trisomy 21, with or without GATA1 mutations. TMD cases without trisomy 21 are rare, and recurrent genetic aberrations that aid in clinical decision-making are scarcely described. We describe here a TMD patient without trisomy 21 or GATA1 mutation in whom single-nucleotide polymorphism analysis of leukemic blasts revealed a novel combined submicroscopic deletion (5q31.1-5q31.3 and 8q23.2q24).


Assuntos
Cromossomos Humanos Par 5/genética , Cromossomos Humanos Par 8/genética , Síndrome de Down/genética , Fator de Transcrição GATA1/genética , Leucemia Megacarioblástica Aguda/genética , Polimorfismo de Nucleotídeo Único/genética , Síndrome de Down/patologia , Humanos , Recém-Nascido , Leucemia Megacarioblástica Aguda/patologia , Prognóstico
4.
Nat Commun ; 15(1): 6025, 2024 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-39019934

RESUMO

Therapy-related myeloid neoplasms (t-MN) arise as a complication of chemo- and/or radiotherapy. Although t-MN can occur both in adult and childhood cancer survivors, the mechanisms driving therapy-related leukemogenesis likely vary across different ages. Chemotherapy is thought to induce driver mutations in children, whereas in adults pre-existing mutant clones are selected by the exposure. However, selective pressures induced by chemotherapy early in life are less well studied. Here, we use single-cell whole genome sequencing and phylogenetic inference to show that the founding cell of t-MN in children starts expanding after cessation of platinum exposure. In patients with Li-Fraumeni syndrome, characterized by a germline TP53 mutation, we find that the t-MN already expands during treatment, suggesting that platinum-induced growth inhibition is TP53-dependent. Our results demonstrate that germline aberrations can interact with treatment exposures in inducing t-MN, which is important for the development of more targeted, patient-specific treatment regimens and follow-up.


Assuntos
Mutação em Linhagem Germinativa , Síndrome de Li-Fraumeni , Segunda Neoplasia Primária , Proteína Supressora de Tumor p53 , Humanos , Proteína Supressora de Tumor p53/genética , Síndrome de Li-Fraumeni/genética , Criança , Segunda Neoplasia Primária/genética , Masculino , Feminino , Compostos de Platina/uso terapêutico , Adulto , Adolescente , Sequenciamento Completo do Genoma , Filogenia , Pré-Escolar , Antineoplásicos/uso terapêutico , Análise de Célula Única
5.
Cell Genom ; 3(9): 100389, 2023 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-37719152

RESUMO

Detection of somatic mutations in single cells has been severely hampered by technical limitations of whole-genome amplification. Novel technologies including primary template-directed amplification (PTA) significantly improved the accuracy of single-cell whole-genome sequencing (WGS) but still generate hundreds of artifacts per amplification reaction. We developed a comprehensive bioinformatic workflow, called the PTA Analysis Toolbox (PTATO), to accurately detect single base substitutions, insertions-deletions (indels), and structural variants in PTA-based WGS data. PTATO includes a machine learning approach and filtering based on recurrence to distinguish PTA artifacts from true mutations with high sensitivity (up to 90%), outperforming existing bioinformatic approaches. Using PTATO, we demonstrate that hematopoietic stem cells of patients with Fanconi anemia, which cannot be analyzed using regular WGS, have normal somatic single base substitution burdens but increased numbers of deletions. Our results show that PTATO enables studying somatic mutagenesis in the genomes of single cells with unprecedented sensitivity and accuracy.

6.
STAR Protoc ; 3(2): 101361, 2022 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-35573477

RESUMO

Mutational signatures have been identified in cancer genomes, providing information about the causes of cancer and treatment vulnerabilities. This protocol describes an assay to determine the genotoxic mechanisms underlying these signatures using cord-blood derived hematopoietic stem and progenitor cells (CB-HSPCs). CB-HSPCs have a low mutation background, enabling sensitive detection of mutations. First, CB-HSPCs are exposed in vitro, sorted, and clonally expanded. This expansion enables whole-genome sequencing to detect the mutation load and respective patterns induced during genotoxic exposure. For complete details on the use and execution of this protocol, please refer to de Kanter et al. (2021).


Assuntos
Sangue Fetal , Células-Tronco Hematopoéticas , Dano ao DNA , Genoma , Humanos , Sequenciamento Completo do Genoma
7.
Cancer Discov ; 12(8): 1860-1872, 2022 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-35678530

RESUMO

Childhood cancer survivors are confronted with various chronic health conditions like therapy-related malignancies. However, it is unclear how exposure to chemotherapy contributes to the mutation burden and clonal composition of healthy tissues early in life. Here, we studied mutation accumulation in hematopoietic stem and progenitor cells (HSPC) before and after cancer treatment of 24 children. Of these children, 19 developed therapy-related myeloid neoplasms (t-MN). Posttreatment HSPCs had an average mutation burden increase comparable to what treatment-naïve cells accumulate during 16 years of life, with excesses up to 80 years. In most children, these additional mutations were induced by clock-like processes, which are also active during healthy aging. Other patients harbored mutations that could be directly attributed to treatments like platinum-based drugs and thiopurines. Using phylogenetic inference, we demonstrate that most t-MN in children originate after the start of treatment and that leukemic clones become dominant during or directly after chemotherapy exposure. SIGNIFICANCE: Our study shows that chemotherapy increases the mutation burden of normal blood cells in cancer survivors. Only few drugs damage the DNA directly, whereas in most patients, chemotherapy-induced mutations are caused by processes similar to those present during normal aging. This article is highlighted in the In This Issue feature, p. 1825.


Assuntos
Antineoplásicos , Segunda Neoplasia Primária , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Criança , Células-Tronco Hematopoéticas/patologia , Humanos , Mieloma Múltiplo/induzido quimicamente , Mieloma Múltiplo/genética , Mutação , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Neoplasias/genética , Segunda Neoplasia Primária/induzido quimicamente , Segunda Neoplasia Primária/genética , Segunda Neoplasia Primária/patologia , Filogenia
8.
Blood Cancer Discov ; 2(5): 484-499, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34642666

RESUMO

Acquisition of oncogenic mutations with age is believed to be rate limiting for carcinogenesis. However, the incidence of leukemia in children is higher than in young adults. Here we compare somatic mutations across pediatric acute myeloid leukemia (pAML) patient-matched leukemic blasts and hematopoietic stem and progenitor cells (HSPCs), as well as HSPCs from age-matched healthy donors. HSPCs in the leukemic bone marrow have limited genetic relatedness and share few somatic mutations with the cell-of-origin of the malignant blasts, suggesting polyclonal hematopoiesis in pAML patients. Compared to normal HSPCs, a subset of pAML cases harbored more somatic mutations and a distinct composition of mutational process signatures. We hypothesize these cases might have arisen from a more committed progenitor. This subset had better outcomes than pAML cases with mutation burden comparable to age-matched healthy HSPCs. Our study provides insights into the etiology and patient stratification of pAML.


Assuntos
Leucemia Mieloide Aguda , Medula Óssea/patologia , Criança , Hematopoese , Células-Tronco Hematopoéticas/patologia , Humanos , Leucemia Mieloide Aguda/genética , Mutação , Adulto Jovem
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