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1.
Blood ; 139(14): 2198-2211, 2022 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-34864916

RESUMO

KMT2A-rearranged (KMT2A-r) infant acute lymphoblastic leukemia (ALL) is a devastating malignancy with a dismal outcome, and younger age at diagnosis is associated with increased risk of relapse. To discover age-specific differences and critical drivers that mediate poor outcome in KMT2A-r ALL, we subjected KMT2A-r leukemias and normal hematopoietic cells from patients of different ages to single-cell multiomics analyses. We uncovered the following critical new insights: leukemia cells from patients <6 months have significantly increased lineage plasticity. Steroid response pathways are downregulated in the most immature blasts from younger patients. We identify a hematopoietic stem and progenitor-like (HSPC-like) population in the blood of younger patients that contains leukemic blasts and form an immunosuppressive signaling circuit with cytotoxic lymphocytes. These observations offer a compelling explanation for the ability of leukemias in young patients to evade chemotherapy and immune-mediated control. Our analysis also revealed preexisting lymphomyeloid primed progenitors and myeloid blasts at initial diagnosis of B-ALL. Tracking of leukemic clones in 2 patients whose leukemia underwent a lineage switch documented the evolution of such clones into frank acute myeloid leukemia (AML). These findings provide critical insights into KMT2A-r ALL and have clinical implications for molecularly targeted and immunotherapy approaches. Beyond infant ALL, our study demonstrates the power of single-cell multiomics to detect tumor intrinsic and extrinsic factors affecting rare but critical subpopulations within a malignant population that ultimately determines patient outcome.


Assuntos
Antineoplásicos , Leucemia Mieloide Aguda , Leucemia-Linfoma Linfoblástico de Células Precursoras , Antineoplásicos/uso terapêutico , Rearranjo Gênico , Humanos , Imunoterapia , Lactente , Leucemia Mieloide Aguda/genética , Proteína de Leucina Linfoide-Mieloide/genética , Proteína de Leucina Linfoide-Mieloide/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética
2.
Pediatr Blood Cancer ; 69(1): e29344, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34550633

RESUMO

Twelvepatients without therapy-related leukemia were studied after completing TOP2 poison chemotherapy in a high-risk neuroblastoma regimen. One patient harbored an inv(11) that was a KMT2A rearrangement. The KMT2A-MAML2 transcript was expressed at low level. The patient was prospectively followed. The inv(11) was undetectable in ensuing samples. Leukemia never developed after a 12.8-year follow-up period. Enriched etoposide-induced TOP2A cleavage in the relevant MAML2 genomic region supports a TOP2A DNA damage mechanism. After completing TOP2 poison chemotherapies, covert KMT2A-R clones may occur in a small minority of patients; however, not all KMT2A rearrangements herald a therapy-related leukemia diagnosis.


Assuntos
Histona-Lisina N-Metiltransferase , Leucemia , Proteína de Leucina Linfoide-Mieloide , Neuroblastoma , Transativadores , Etoposídeo/administração & dosagem , Seguimentos , Rearranjo Gênico , Humanos , Leucemia/genética , Proteína de Leucina Linfoide-Mieloide/genética , Neuroblastoma/tratamento farmacológico , Neuroblastoma/genética , Fatores de Transcrição/genética
3.
Genome Res ; 27(7): 1238-1249, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28385713

RESUMO

Type II topoisomerases orchestrate proper DNA topology, and they are the targets of anti-cancer drugs that cause treatment-related leukemias with balanced translocations. Here, we develop a high-throughput sequencing technology to define TOP2 cleavage sites at single-base precision, and use the technology to characterize TOP2A cleavage genome-wide in the human K562 leukemia cell line. We find that TOP2A cleavage has functionally conserved local sequence preferences, occurs in cleavage cluster regions (CCRs), and is enriched in introns and lincRNA loci. TOP2A CCRs are biased toward the distal regions of gene bodies, and TOP2 poisons cause a proximal shift in their distribution. We find high TOP2A cleavage levels in genes involved in translocations in TOP2 poison-related leukemia. In addition, we find that a large proportion of genes involved in oncogenic translocations overall contain TOP2A CCRs. The TOP2A cleavage of coding and lincRNA genes is independently associated with both length and transcript abundance. Comparisons to ENCODE data reveal distinct TOP2A CCR clusters that overlap with marks of transcription, open chromatin, and enhancers. Our findings implicate TOP2A cleavage as a broad DNA damage mechanism in oncogenic translocations as well as a functional role of TOP2A cleavage in regulating transcription elongation and gene activation.


Assuntos
Dano ao DNA , DNA Topoisomerases Tipo II/metabolismo , Loci Gênicos , Leucemia/enzimologia , Proteínas de Neoplasias/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Elongação da Transcrição Genética , DNA Topoisomerases Tipo II/genética , Humanos , Células K562 , Leucemia/genética , Leucemia/patologia , Proteínas de Neoplasias/genética , Proteínas de Ligação a Poli-ADP-Ribose/genética , RNA Longo não Codificante/biossíntese , RNA Longo não Codificante/genética
4.
Oncogene ; 38(13): 2241-2262, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30478448

RESUMO

The poor outcomes in infant acute lymphoblastic leukemia (ALL) necessitate new treatments. Here we discover that EIF4E protein is elevated in most cases of infant ALL and test EIF4E targeting by the repurposed antiviral agent ribavirin, which has anticancer properties through EIF4E inhibition, as a potential treatment. We find that ribavirin treatment of actively dividing infant ALL cells on bone marrow stromal cells (BMSCs) at clinically achievable concentrations causes robust proliferation inhibition in proportion with EIF4E expression. Further, we find that ribavirin treatment of KMT2A-rearranged (KMT2A-R) infant ALL cells and the KMT2A-AFF1 cell line RS4:11 inhibits EIF4E, leading to decreases in oncogenic EIF4E-regulated cell growth and survival proteins. In ribavirin-sensitive KMT2A-R infant ALL cells and RS4:11 cells, EIF4E-regulated proteins with reduced levels of expression following ribavirin treatment include MYC, MCL1, NBN, BCL2 and BIRC5. Ribavirin-treated RS4:11 cells exhibit impaired EIF4E-dependent nuclear to cytoplasmic export and/or translation of the corresponding mRNAs, as well as reduced phosphorylation of the p-AKT1, p-EIF4EBP1, p-RPS6 and p-EIF4E signaling proteins. This leads to an S-phase cell cycle arrest in RS4:11 cells corresponding to the decreased proliferation. Ribavirin causes nuclear EIF4E to re-localize to the cytoplasm in KMT2A-AFF1 infant ALL and RS4:11 cells, providing further evidence for EIF4E inhibition. Ribavirin slows increases in peripheral blasts in KMT2A-R infant ALL xenograft-bearing mice. Ribavirin cooperates with chemotherapy, particularly L-asparaginase, in reducing live KMT2A-AFF1 infant ALL cells in BMSC co-cultures. This work establishes that EIF4E is broadly elevated across infant ALL and that clinically relevant ribavirin exposures have preclinical activity and effectively inhibit EIF4E in KMT2A-R cases, suggesting promise in EIF4E targeting using ribavirin as a means of treatment.


Assuntos
Fator de Iniciação 4E em Eucariotos/genética , Terapia de Alvo Molecular/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Ribavirina/uso terapêutico , Linhagem Celular Tumoral , Pré-Escolar , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Fator de Iniciação 4E em Eucariotos/fisiologia , Perfilação da Expressão Gênica , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Humanos , Indóis , Lactente , Análise em Microsséries , Família Multigênica/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Biossíntese de Proteínas/efeitos dos fármacos , Pirróis/uso terapêutico , Transdução de Sinais/efeitos dos fármacos
5.
Biomech Model Mechanobiol ; 11(1-2): 119-29, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21369918

RESUMO

Flow and stresses induced by blood flow acting on the blood cellular constituents can be represented to a certain extent by a continuum mechanics approach down to the order of the µm level. However, the molecular effects of, e.g., adhesion/aggregation bonds of blood clotting can be on the order of nm. The coupling of the disparate length and timescales between such molecular levels and macroscopic transport represents a major computational challenge. To address this challenge, a multiscale numerical approach based on discrete particle dynamics (DPD) methodology derived from molecular dynamics (MD) principles is proposed. The feasibility of the approach was firstly tested for its ability to simulate viscous flow conditions. Simulations were conducted in low Reynolds numbers flows (Re = 25-33) through constricted tubes representing blood vessels with various degrees of stenosis. Multiple discrete particles interacting with each other were simulated, with 1.24-1.36 million particles representing the flow domain and 0.4 million particles representing the vessel wall. The computation was carried out on the massive parallel supercomputer NY BlueGene/L employing NAMD-a parallel MD package for high performance computing (HPC). Typical recirculation zones were formed distal to the stenoses. The velocity profiles and recirculation zones were in excellent agreement with computational fluid dynamics (CFD) 3D Navier-Stokes viscous fluid flow simulations and with classic numerical and experimental results by YC Fung in constricted tubes. This feasibility analysis demonstrates the potential of a methodology that widely departs from a continuum approach to simulate multiscale phenomena such as flow induced blood clotting.


Assuntos
Simulação por Computador , Estenose Coronária/fisiopatologia , Hemorreologia/fisiologia , Hidrodinâmica , Modelos Cardiovasculares , Velocidade do Fluxo Sanguíneo/fisiologia , Circulação Coronária/fisiologia , Simulação de Dinâmica Molecular , Nanoestruturas , Tamanho da Partícula , Viscosidade
6.
Nano Lett ; 7(8): 2267-71, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17608442

RESUMO

This paper presents first-principles calculations for ultrasmall ZnO one-dimensional nanostructures. The calculations were done on ZnO nanowires and single-walled nanotubes with n atoms per periodic unit, where one periodic unit is made up of two ZnO layers. The calculations show that, for small n, a single-walled nanotube has lower energy than a nanowire. A crossover point near n = 38 is predicted. Vibrations and vibrational entropy of competing structures is discussed.


Assuntos
Cristalização/métodos , Modelos Químicos , Modelos Moleculares , Nanoestruturas/química , Nanoestruturas/ultraestrutura , Nanotecnologia/métodos , Óxido de Zinco/química , Simulação por Computador , Substâncias Macromoleculares/química , Teste de Materiais , Conformação Molecular , Tamanho da Partícula , Propriedades de Superfície , Vibração
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