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1.
Artigo em Inglês | MEDLINE | ID: mdl-36673942

RESUMO

It is known that occupational exposure to specific agents is associated with leukemia. However, whether the occupational risks of leukemia differ among various industrial groups remains unclear. Therefore, the purpose of this study was to elucidate the occupational risks of leukemia among different worker groups by industry. Data for a total of 11,050,398 people from the National Health Insurance System's claim data from 2007 to 2015 were analyzed. By cohort inclusion of workers whose industry had not changed for three years and with total workers as a control group, the risk for a specific industry group was expressed as an age-standardized incidence ratio (SIR). Among groups by industry, 'Manufacture of motor vehicles and engines for motor vehicles', 'Sale of motor vehicle parts and accessories', and 'Personal care services' showed significantly higher SIRs. In division analysis, the 'Manufacture of other machinery and equipment' and 'Waste collection, treatment and disposal activities' divisions showed significantly higher SIRs than other divisions. We identified an increased risk of leukemia in workers of certain industries in Korea. Based on the results of this study, it is necessary to create a policy to protect workers at risk of leukemia. Various additional studies are needed to protect workers by revealing more precise relationships between individual hazardous substances, processes, and leukemia.


Assuntos
Leucemia , Doenças Profissionais , Exposição Ocupacional , Humanos , Estudos de Coortes , Estudos Retrospectivos , Doenças Profissionais/epidemiologia , Doenças Profissionais/etiologia , Leucemia/epidemiologia , Leucemia/complicações , Exposição Ocupacional/efeitos adversos , Incidência , República da Coreia/epidemiologia
2.
Medicine (Baltimore) ; 102(2): e32576, 2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36637928

RESUMO

Infection is a common complication of leukemia patients undergoing chemotherapy. Blood culture results are often needed to guide clinical use, but repeated sampling is often necessary to improve the positive rate and eliminate contamination. The purpose of this paper is to find predictive factors of blood culture results among clinical and laboratory indicators and try to establish a prediction model, so as to better choose the time of blood culture examination, predict the results, and better guide clinical treatment. We retrospectively collected clinical and laboratory data of febrile acute leukemia patients undergoing chemotherapy. The samples were randomly assigned to the training set and the validation set, and the prediction model was constructed from the training set. The calibration curve was made in the validation set and the Hosmer-Lemeshow test was performed to evaluate the prediction performance of the prediction model. A total of 229 patients were included. Univariate and multivariate analyses suggested that temperature at fever and procalcitonin were variables of significant difference between positive and negative blood culture patients. The sensitivity of the 2 variables for predicting blood culture results was high, but the specificity was low. In the process of external validation, the predictive ability of the constructed prediction model to the blood culture results was low. This study identified clinical and laboratory parameters associated with blood culture outcomes, but the predictive model established has low predictive accuracy in external validation.


Assuntos
Hemocultura , Leucemia , Humanos , Estudos Retrospectivos , Leucemia/complicações , Leucemia/tratamento farmacológico
3.
Open Biol ; 13(1): 220232, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36629017

RESUMO

The Mixed-Lineage Leukaemia (MLL/KMT2A) gene is frequently rearranged in childhood and adult acute leukaemia (AL) and in secondary leukaemias occurring after therapy with DNA topoisomerase targeting anti-cancer agents such as etoposide (t-AL). MLL/KMT2A chromosome translocation break sites in AL patients fall within an 8 kb breakpoint cluster region (BCR). Furthermore, MLL/KMT2A break sites in t-AL frequently occur in a much smaller region, or hotspot, towards the 3' end of the BCR, close to the intron 11/exon 12 boundary. These findings have prompted considerable effort to uncover mechanisms behind the apparent fragility of the BCR and particularly the t-AL hotspot. Recent genome-wide analyses have demonstrated etoposide-induced DNA cleavage within the BCR, and it is tempting to conclude that this cleavage explains the distribution of translocation break sites in t-AL. However, the t-AL hotspot and the centre of the observed preferential DNA cleavage are offset by over 250 nucleotides, suggesting additional factors contribute to the distribution of t-AL break sites. We review these recent genomic datasets along with older experimental results, analysis of TOP2 DNA cleavage site preferences and DNA secondary structure features that may lead to break site selection in t-AL MLL/KMT2A translocations.


Assuntos
Estudo de Associação Genômica Ampla , Leucemia , Humanos , Etoposídeo/farmacologia , DNA Topoisomerases Tipo II , DNA , Translocação Genética , Leucemia/genética
4.
Genes (Basel) ; 14(1)2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36672872

RESUMO

Early-stage leukemia identification is crucial for effective disease management and leads to an improvement in the survival of leukemia patients. Approaches based on cutting-edge biomarkers with excellent accuracy in body liquids provide patients with the possibility of early diagnosis with high sensitivity and specificity. Non-coding RNAs have recently received a great deal of interest as possible biomarkers in leukemia due to their participation in crucial oncogenic processes such as proliferation, differentiation, invasion, apoptosis, and their availability in body fluids. Recent studies have revealed a strong correlation between leukemia and the deregulated non-coding RNAs. On this basis, these RNAs are also great therapeutic targets. Based on these advantages, we tried to review the role of non-coding RNAs in leukemia. Here, the significance of several non-coding RNA types in leukemia is highlighted, and their potential roles as diagnostic, prognostic, and therapeutic targets are covered.


Assuntos
Leucemia , Humanos , Biomarcadores , Leucemia/diagnóstico , Leucemia/genética , Leucemia/terapia , RNA , Prognóstico
5.
Int J Mol Sci ; 24(2)2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36674556

RESUMO

The modification of chitosan (CS) has greatly expanded its application in the field of medicine. In this study, low-molecular-weight chitosan was modified with arginine (Arg) by a simple method. The identification by the Fourier transform infrared spectra (FTIR) showed that Arg was successfully covalently attached to the CS. Interestingly, Arg-CS was identified as nanoparticles by atomic force microscopy (AFM) and transmission electron microscopy (TEM), whose particle size was 75.76 ± 12.07 nm based on Dynamic Light Scattering (DLS) characterization. Then, whether the prepared Arg-CS nanoparticles could encapsulate and deliver siRNA safely was investigated. Arg-CS was found to be able to encapsulate siRNAs in vitro via electrostatic interaction with siRNA; the Arg-CS/siRNA complex was safe for L1210 leukemia cells. Therefore, modification of chitosan by Arg produces novel nanoparticles to deliver siRNA into leukemia cells. This is the first time to identify Arg-CS as nanoparticles and explore their ability to deliver Rhoa siRNA into T-cell acute lymphoblastic leukemia (T-ALL) cells to advance therapies targeting Rhoa in the future.


Assuntos
Quitosana , Leucemia , Nanopartículas , Animais , Camundongos , RNA Interferente Pequeno/genética , Arginina , Leucemia/genética , Leucemia/terapia , Tamanho da Partícula , Espectroscopia de Infravermelho com Transformada de Fourier
7.
Support Care Cancer ; 31(2): 109, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36625831

RESUMO

PURPOSE: Neurocognitive impairment is frequently observed among survivors of childhood acute lymphoblastic leukemia (ALL) within the domains of attention, working memory, processing speed, executive functioning, and learning and memory. However, few studies have characterized the trajectory of treatment-induced changes in neurocognitive function beginning in the first months of treatment, to test whether early changes predict impairment among survivors. If correct, we hypothesize that those children who are most susceptible to early impairment would be ideal subjects for clinical trials testing interventions designed to protect against treatment-related neurocognitive decline. METHODS: In this pilot study, we prospectively assessed neurocognitive functioning (attention, working memory, executive function, visual learning, and processing speed), using the Cogstate computerized battery at six time points during the 2 years of chemotherapy treatment and 1-year post-treatment (Dana-Farber Cancer Institute ALL Consortium protocol 11-001; NCT01574274). RESULTS: Forty-three patients with ALL consented to serial neurocognitive testing. Of the 31 participants who remained on study through the final time point, 1 year after completion of chemotherapy, 28 (90%) completed at least five of six planned Cogstate testing time points. Performance and completion checks indicated a high tolerability (≥ 88%) for all subtests. One year after completion of treatment, 10 of 29 patients (34%) exhibited neurocognitive function more than 2 standard deviations below age-matched norms on one or more Cogstate subtests. CONCLUSIONS: Serial collection of neurocognitive data (within a month of diagnosis with ALL, during therapy, and 1-year post-treatment) is feasible and can be informative for evaluating treatment-related neurocognitive impairment.


Assuntos
Função Executiva , Leucemia , Criança , Humanos , Estudos de Viabilidade , Memória de Curto Prazo , Testes Neuropsicológicos , Projetos Piloto , Estudos Prospectivos
9.
Clin Lab ; 69(1)2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36649522

RESUMO

BACKGROUND: The goal was to improve the understanding of mixed phenotypic acute leukemia (MPAL) complicated with plasmacytoid dendritic cell (PDC) proliferation. METHODS: A case of mixed phenotype acute leukemia with plasmacytoid dendritic cell hyperplasia was reported. The clinical characteristics, treatment, and prognosis were analyzed by reviewing relevant literature. RESULTS: The patient was a young female with clinical manifestations of splenomegaly and lymph node enlargement. The bone marrow smear showed hyperactive proliferation, 95% of protoblastic cells. The protoblastic cell body is large, more cell mass, stained gray blue, a small amount of azurophilicgranule can be seen in some cytoplasm, pseudopodia, drag tail, and other phenomena. The nucleus was twisted and folded. Chromatin is fine with nucleoli and Auer rods seen in the cytoplasm. Immune typing: Abnormal primordial cells accounted for 44.75%, and the primordial cells expressed both myeloid markers (CD33, CD13, MPO) and T-series markers (CD7, CD5, Ccd3), which were considered MPAL (M/T) according to WHO diagnostic criteria. In addition, a group of plasmoid dendritic cells occupied an increased proportion of 10.31% of nuclear cells. No obvious phenotypic abnormalities were observed. BCR/ABL fusion genes P190/P210 were negative. NRAS, NOTCH1, and DNMT3A mutations were detected by polymerase chain reaction. Combined with the above results, acute mixed cell leukemia (M/T) with plasmacytoid dendritic cell proliferation was diagnosed. CONCLUSIONS: The diagnosis of mixed phenotype acute leukemia with plasmacytoid dendritic cell proliferation needs to be integrated with clinical manifestations, cytomorphology, immunology, cytogenetics, and molecular biology, etc. Disease should be diagnosed and treated as early as possible.


Assuntos
Leucemia , Feminino , Humanos , Prognóstico , Doença Aguda , Fenótipo , Células Dendríticas , Proliferação de Células
10.
J Enzyme Inhib Med Chem ; 38(1): 2157825, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36629421

RESUMO

In this research, two novel series of dibenzo[b,f]azepines (14 candidates) were designed and synthesised based on the rigidification principle and following the reported doxorubicin's pharmacophoric features. The anti-proliferative activity was evaluated at the NCI against a panel of 60 cancer cell lines. Further, the promising candidates (5a-g) were evaluated for their ability to inhibit topoisomerase II, where 5e was noticed to be the most active congener. Moreover, its cytotoxicity was evaluated against leukaemia SR cells. Also, 5e arrested the cell cycle at the G1 phase and increased the apoptosis ratio by 37.34%. Furthermore, in vivo studies of 5e showed the inhibition of tumour proliferation and the decrease in its volume. Histopathology and liver enzymes were examined as well. Besides, molecular docking, physicochemical, and pharmacokinetic properties were carried out. Finally, a SAR study was discussed to open the gate for further optimisation of the most promising candidate (5e).HighlightsTwo novel series of dibenzo[b,f]azepines were designed and synthesised based on the rigidification principle in drug design.The anti-proliferative activity was evaluated at the NCI against a panel of 60 cancer cell lines.5e was the most active anti-topo II congener (IC50 = 6.36 ± 0.36 µM).5e was evaluated against leukaemia SR cells and its cytotoxic effect was confirmed (IC50 = 13.05 ± 0.62 µM).In vivo studies of 5e significantly inhibited tumour proliferation by 62.7% and decreased tumour volume to 30.1 mm3 compared to doxorubicin treatment.


Assuntos
Antineoplásicos , Leucemia , Humanos , Inibidores da Topoisomerase II/química , Relação Estrutura-Atividade , Substâncias Intercalantes/farmacologia , Simulação de Acoplamento Molecular , Linhagem Celular Tumoral , Azepinas/farmacologia , Antineoplásicos/química , Doxorrubicina/farmacologia , DNA , Proliferação de Células , Estrutura Molecular , Ensaios de Seleção de Medicamentos Antitumorais , DNA Topoisomerases Tipo II/metabolismo
11.
Drug Des Devel Ther ; 17: 1-13, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36636745

RESUMO

Objective: This study aimed to develop a binary nanodrug-delivery system decorated with aptamers (APs) and transferrin (Tf) and loaded with daunorubicin (Drn) and luteolin (Lut) for the treatment of leukemia. Methods: Oligonucleotide AP- and Tf-contaiing ligands were designed and synthesized separately. AP-decorated Drn-loaded nanoparticles (AP-Drn NPs) and Tf-Lut NPs were prepared by self-assembly. An AP- and Tf-codecorated Drn- and Lut-coloaded nanodrug-delivery system (AP/Tf-Drn/Lut NPs) was prepared by self-assembly of AP-Drn NPs and Tf-Lut NPs. In vitro and in vivo efficiency of the system was evaluated on leukemia cell line and cell-bearing mouse model in comparison with single ligand-decorated, single drug-loaded and free-drug formulations. Results: AP/Tf-Drn/Lut NPs were spherical and nanosized (187.3±5.3 nm) and loaded with about 85% of drugs. In vitro cytotoxicity of AP/Tf-Drn/Lut NPs was remarkably higher than single ligand-decorated ones. Double drug-loaded AP/Tf-Drn/Lut NPs exhibited higher tumor-cell inhibition than single drug-loaded ones, which showed a synergic effect of the two drugs. AP/Tf-Drn/Lut NPs achieved the most efficient antileukemic activity and absence of toxicity in vivo. Conclusion: The present study showed that AP/Tf-Drn/Lut NPs are a promising drug-delivery system for targeted treatment of leukemia, due to the synergic effect of the two drugs in this system. The limitations of this system include stability during large-scale production and application from bench to bedside.


Assuntos
Leucemia , Nanopartículas , Camundongos , Animais , Daunorrubicina/farmacologia , Luteolina , Transferrina/metabolismo , Ligantes , Sistemas de Liberação de Medicamentos , Leucemia/tratamento farmacológico , Nanopartículas/uso terapêutico , Oligonucleotídeos , Linhagem Celular Tumoral
12.
Reprod Health ; 20(1): 4, 2023 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-36593491

RESUMO

BACKGROUND: The risk of premature ovarian insufficiency (POI) is increased in adolescent and young adult (AYA) cancer survivors, with the prevalence depending on cancer diagnosis, treatment, and patient factors. Prior studies are limited by sample size and type of cancer included. The objective of this study was to assess the risk of POI in female AYA survivors of non-gynecologic cancers, using a population-based approach. METHODS: This population-based retrospective cohort study comprises 21,666 females, 15-39 years old, diagnosed with a single non-gynecologic cancer in Ontario, Canada from 1995 to 2015. Through health administrative data linkage, participants were followed until their 40th birthday, December 31, 2018, bilateral oophorectomy, loss of health insurance eligibility or death. Each cancer survivor was matched to 5 females who were not diagnosed with cancer (unexposed, n = 108,330). Women with bilateral oophorectomy or a prior menopause diagnosis were excluded. POI was identified through use of the ICD-9 code for menopause (ICD9-627). Modified Poisson regression models were used to calculate the adjusted relative risk (aRR) of POI for AYA cancer survivors compared to unexposed individuals, adjusted for income, parity, age, and immigration status. RESULTS: The occurrence of POI was higher in survivors of AYA cancer versus unexposed patients (5.4% vs. 2.2%). Survivors of AYA cancer had an increased risk of POI relative to unexposed patients (aRR 2.49; 95% CI 2.32-2.67). Risk varied by type of cancer: breast (4.32; 3.84-4.86), non-Hodgkin's lymphoma (3.77; 2.88-4.94), Hodgkin's lymphoma (2.37; 1.91-2.96), leukemia (14.64; 10.50-20.42), thyroid (1.26; 1.09-1.46) and melanoma (1.04; 0.82-1.32). Risk varied by age at time of cancer diagnosis, with a higher risk among females diagnosed at age 30-39 years (3.07; 2.80-3.35) than aged 15-29 years (1.75; 1.55-1.98). CONCLUSIONS: AYA survivors of non-gynecologic cancers are at an increased risk of POI, particularly survivors of lymphomas, leukemia, breast, and thyroid cancer. The risk of POI is increased for those diagnosed with cancer at an older age. These results should inform reproductive counseling of female AYAs diagnosed with cancer.


Premature ovarian insufficiency is the onset of premature menopause in individuals less than 40-years-old. Previous research has shown that there is a higher risk of premature ovarian insufficiency in adolescent and young adult cancer survivors, due to the toxicity of cancer treatments on reproductive organs. Prior research was limited in its applicability by having small sample sizes, only including childhood cancer, excluding young adults, and studying fewer types of cancer. This study was conducted using a large population-based approach, on all females aged 15­39 years old with cancer in Ontario, Canada from 1995 to 2015. We found that there was nearly a 2.5 times greater risk of premature ovarian insufficiency in cancer survivors compared patients without cancer. Compared to patients without cancer, this risk was highest for survivors of leukemia (14 times higher risk), followed by breast cancer (4 times higher risk), lymphomas (2­4 times higher risk), and thyroid cancer (1.2 times higher risk). There is no increased risk in melanoma survivors. The risk was higher in individuals diagnosed with cancer at a later age (30­39 years), with a risk 3 times higher than the population without cancer, while a younger age of diagnosis (15­29 years) carries a risk only 1.75 times higher than the population without cancer. These results should help improve healthcare provider and patient understanding of the risk of premature ovarian insuficiency in young cancer survivors, and guide counseling at the time of cancer diagnosis and during survivorship on future reproductive function.


Assuntos
Leucemia , Neoplasias , Insuficiência Ovariana Primária , Gravidez , Humanos , Feminino , Adolescente , Adulto Jovem , Adulto , Estudos de Coortes , Estudos Retrospectivos , Neoplasias/complicações , Sobreviventes , Insuficiência Ovariana Primária/epidemiologia , Insuficiência Ovariana Primária/etiologia , Leucemia/complicações , Ontário/epidemiologia
13.
J Pediatr Hematol Oncol ; 45(1): e150-e153, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36598968

RESUMO

BACKGROUND: In the 2016 ESPGHAN recommendations on how to deal with hepatitis E virus infection in immunocompromised children, patients treated with chemotherapy were not specifically mentioned. OBSERVATIONS: Two teenagers treated with chemotherapy for acute leukemia and medulloblastoma, respectively, were diagnosed with hepatic cytolysis. After numerous investigations hepatitis E was found, limiting the good progress of the chemotherapy treatment. CONCLUSION: In the case of liver cytolysis in immunocompromised children treated with chemotherapy, hepatitis E virus infection has to be promptly diagnosed.


Assuntos
Vírus da Hepatite E , Hepatite E , Leucemia , Criança , Adolescente , Humanos , Hepatite E/diagnóstico , Hepatite E/tratamento farmacológico , Vírus da Hepatite E/genética , Hospedeiro Imunocomprometido
14.
Cell Stem Cell ; 30(1): 3-4, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36608677

RESUMO

Chemical modifications of RNA are regulated by a series of readers, writers, and erasers that dictate gene expression. Two new studies in Cell Stem Cell1,2identify roles for the N6-methyladenosine (m6A) methyltransferase METTL16 and the m6A reader IGF2BP2 in leukemia-initiating cells, illuminating exciting new therapeutic targets for leukemia.


Assuntos
Leucemia , RNA , Humanos , RNA/genética , RNA/metabolismo , Metilação , Metiltransferases/genética , Leucemia/genética , Células-Tronco/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo
15.
Immun Inflamm Dis ; 11(1): e725, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36705414

RESUMO

BACKGROUND: Circular RNAs (circRNAs) are a new category of endogenous non-protein coding RNAs (ncRNAs), and show the characteristics of high conservation, stability, and tissue specificity. Due to rapid advances in next-generation sequencing and transcriptome profiling technologies, circRNAs have been widely discovered in many organisms and participated in the development and progress of a variety of diseases. As a type of molecular sponge, circRNAs mainly absorb micro RNAs competitively and interplay with RNA-binding proteins to modulate the splicing as well as transcription of target genes. METHODS: This review is based on a literature search using the Medline database. Search terms used were "circular RNAs and leukemia," "circRNAs and leukemia," "circRNAs and acute lymphoblastic leukemia," "circRNAs and chronic lymphoblastic leukemia," "circRNAs and acute myeloid leukemia," "circRNAs and chronic myeloid leukemia," and "circRNAs, biomarker, and hematological system." RESULTS: CircRNAs have been proven as potential biomarkers and therapeutic targets in a variety of tumors. Recent research has found that circRNAs aberrantly exist in hematological cancers, especially leukemia, and are significantly associated with the incidence, progress, and metastasis of diseases as well as the prognosis of patients. CONCLUSION: The current work summarizes the latest findings on circRNAs in various types of leukemia, aiming to propose prospective therapies and new drug screening methods for the treatment of leukemia.


Assuntos
Leucemia , MicroRNAs , Neoplasias , Humanos , RNA Circular/genética , Leucemia/diagnóstico , Leucemia/genética , Neoplasias/genética , Biomarcadores
17.
Eur J Med Chem ; 248: 115093, 2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-36645983

RESUMO

Eleven-Nineteen-Leukemia Protein (ENL) containing YEATS domain, a potential drug target, has emerged as a reader of lysine acetylation. SGC-iMLLT bearing with benzimidazole scaffold was identified as an effective ENL inhibitor, but with weak activity against mixed-lineage leukemia (MLL)-rearranged cells proliferation. In this study, a series of compounds were designed and synthesized by structural optimization on SGC-iMLLT. All the compounds have been evaluated for their ENL inhibitory activities. The results showed that compounds 13, 23 and 28 are the most potential ones with the IC50 values of 14.5 ± 3.0 nM, 10.7 ± 5.3 nM, and 15.4 ± 2.2 nM, respectively, similar with that of SGC-iMLLT. They could interact with ENL protein and strengthen its thermal stability in vitro. Among them, compound 28 with methyl phenanthridinone moiety replacement of indazole in SGC-iMLLT, exhibited significantly inhibitory activities towards MV4-11 and MOLM-13 cell lines with IC50 values of 4.8 µM and 8.3 µM, respectively, exhibiting ∼7 folds and ∼9 folds more potent inhibition of cell growth than SGC-iMLLT. It could also increase the ENL thermal stability while SGC-iMLLT had no obvious effect on leukemia cells. Moreover, compound 28 could downregulate the expression of target gene MYC either alone or in combination with JQ-1 in cells, which was more effective than SGC-iMLLT. Besides, in vivo pharmacokinetic studies showed that the PK properties for compound 28 was much improved over that of SGC-iMLLT. These observations suggested compound 28 was a potential ligand for ENL-related MLL chemotherapy.


Assuntos
Leucemia , Fatores de Transcrição , Humanos , Fatores de Transcrição/metabolismo , Histonas/metabolismo , Leucemia/tratamento farmacológico , Leucemia/metabolismo , Linhagem Celular , Domínios Proteicos , Proteína de Leucina Linfoide-Mieloide/metabolismo
19.
Nat Commun ; 14(1): 448, 2023 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-36707513

RESUMO

Chromatin regulators are frequently mutated in human cancer and are attractive drug targets. They include diverse proteins that share functional domains and assemble into related multi-subunit complexes. To investigate functional relationships among these regulators, here we apply combinatorial CRISPR knockouts (KOs) to test over 35,000 gene-gene pairings in leukemia cells, using a library of over 300,000 constructs. Top pairs that demonstrate either compensatory non-lethal interactions or synergistic lethality enrich for paralogs and targets that occupy the same protein complex. The screen highlights protein complex dependencies not apparent in single KO screens, for example MCM histone exchange, the nucleosome remodeling and deacetylase (NuRD) complex, and HBO1 (KAT7) complex. We explore two approaches to NuRD complex inactivation. Paralog and non-paralog combinations of the KAT7 complex emerge as synergistic lethal and specifically nominate the ING5 PHD domain as a potential therapeutic target when paired with other KAT7 complex member losses. These findings highlight the power of combinatorial screening to provide mechanistic insight and identify therapeutic targets within redundant networks.


Assuntos
Cromatina , Leucemia , Humanos , Cromatina/genética , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/metabolismo , Montagem e Desmontagem da Cromatina , Leucemia/tratamento farmacológico , Leucemia/genética , Histona Acetiltransferases/metabolismo
20.
Cell Mol Life Sci ; 80(1): 23, 2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36598580

RESUMO

Histone lysine-specific methyltransferase 2 (KMT2A-D) proteins, alternatively called mixed lineage leukemia (MLL1-4) proteins, mediate positive transcriptional memory. Acting as the catalytic subunits of human COMPASS-like complexes, KMT2A-D methylate H3K4 at promoters and enhancers. KMT2A-D contain understudied highly conserved triplets and a quartet of plant homeodomains (PHDs). Here, we show that all clustered (multiple) PHDs localize to the well-defined loci of H3K4me3 and H3 acetylation-rich active promoters and enhancers. Surprisingly, we observe little difference in binding pattern between PHDs from promoter-specific KMT2A-B and enhancer-specific KMT2C-D. Fusion of the KMT2A CXXC domain to the PHDs drastically enhances their preference for promoters over enhancers. Hence, the presence of CXXC domains in KMT2A-B, but not KMT2C-D, may explain the promoter/enhancer preferences of the full-length proteins. Importantly, targets of PHDs overlap with KMT2A targets and are enriched in genes involved in the cancer pathways. We also observe that PHDs of KMT2A-D are mutated in cancer, especially within conserved folding motifs (Cys4HisCys2Cys/His). The mutations cause a domain loss-of-function. Taken together, our data suggest that PHDs of KMT2A-D guide the full-length proteins to active promoters and enhancers, and thus play a role in positive transcriptional memory.


Assuntos
Leucemia , Neoplasias , Humanos , Histonas/genética , Histonas/metabolismo , Acetilação , Dedos de Zinco PHD , Neoplasias/genética
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