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1.
Exp Cell Res ; 421(2): 113401, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36306826

RESUMO

Leukemia is a type of blood cancer characterized by high genetic heterogeneity and fatality. While chemotherapy remains the primary form of treatment for leukemia, its effectiveness was profoundly diminished by the genetic heterogeneity and cytogenetic abnormalities of leukemic cells. Therefore, there is an unmet need to develop precision medicine for leukemia with distinct genetic backgrounds. Zebrafish (Danio rerio), a freshwater fish with exceptional feasibility in genome editing, is a powerful tool for rapid human cancer modeling. In the past decades, zebrafish have been adopted in modeling human leukemia, exploring the molecular mechanisms of underlying genetic abnormalities, and discovering novel therapeutic agents. Although many recurrent mutations of leukemia have been modeled in zebrafish for pathological study and drug discovery, its great potential in leukemia modeling was not yet fully exploited, particularly in precision medicine. In this review, we evaluated the current zebrafish models of leukemia/pre-leukemia and genetic techniques and discussed the potential of zebrafish models with novel techniques, which may contribute to the development of zebrafish as a disease model for precision medicine in treating leukemia.


Assuntos
Leucemia , Neoplasias , Animais , Humanos , Peixe-Zebra/genética , Medicina de Precisão , Modelos Animais de Doenças , Leucemia/genética , Leucemia/patologia
2.
Cancer Res ; 82(22): 4153-4163, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36098964

RESUMO

Menin is necessary for the formation of the menin/mixed lineage leukemia (MLL) complex and is recruited directly to chromatin. Menin is an important tumor suppressor in several cancer types, including lung cancer. Here, we investigated the role of MLL in menin-regulated lung tumorigenesis. Ablation of MLL suppressed KrasG12D-induced lung tumorigenesis in a genetically engineered mouse model. MLL deficiency decreased histone H3 lysine 4 trimethylation (H3K4me3) and subsequently suppressed expression of the Ras protein-specific guanine nucleotide-releasing factor 1 (Rasgrf1) gene. Rasgrf1 was essential for the GTP-bound active state of Kras and the activation of Kras downstream pathways as well as their cancer-promoting activities. MI-3, a small-molecule inhibitor targeting MLL, specifically inhibited the growth of Kras-mutated lung cancer cells in vitro and in vivo with minimal effect on wild-type Kras lung cancer growth. Together, these results demonstrate a novel tumor promoter function of MLL in mutant Kras-induced lung tumorigenesis and further indicate that specific blockade of the MLL-Rasgrf1 pathway may be a potential therapeutic strategy for the treatment of tumors containing Kras mutations. SIGNIFICANCE: Activation of mutant Kras is dependent on MLL-mediated epigenetic regulation of Rasgrf1, conferring sensitivity to small-molecule inhibition of MLL in Kras-driven lung cancer.


Assuntos
Epigênese Genética , Neoplasias Pulmonares , Proteína de Leucina Linfoide-Mieloide , ras-GRF1 , Animais , Camundongos , Transformação Celular Neoplásica/metabolismo , Epigênese Genética/genética , Epigênese Genética/fisiologia , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Leucemia/genética , Leucemia/patologia , Pulmão/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/genética , Proteína de Leucina Linfoide-Mieloide/genética , Proteína de Leucina Linfoide-Mieloide/metabolismo , ras-GRF1/genética , ras-GRF1/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Carcinogênese/genética , Carcinogênese/metabolismo , Mutação
3.
J Med Chem ; 65(19): 13413-13435, 2022 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-36173787

RESUMO

Introduction of the N,N-dimethylaminoethoxy group to pyrido[3,2-d]pyrimidine led to the discovery of menin-mixed lineage leukemia (MLL) interaction inhibitor C20. C20 showed strong binding affinity to menin protein and achieved sub-micromolar potency in cell growth inhibition. C20 had good selectivity for the inhibition of the interaction between menin and MLL in the kinase profile evaluation. Pharmacokinetic studies demonstrated that C20 possessed good stability and low clearance rate in liver microsomes and acceptable bioavailability in rats. Subsequent oral administration of C20 showed potent antitumor activity in the MV4;11 subcutaneous xenograft models of MLL-rearranged leukemia. The docking study showed that C20 bound highly with menin, and the N,N-dimethylaminoethoxy group occupied the F9 pocket of menin. This study proved that introducing a hydrophilic group into the F9 pocket of menin would be a new strategy for the design of menin-MLL interaction inhibitors with potent binding affinity and improved physical properties.


Assuntos
Leucemia , Proteína de Leucina Linfoide-Mieloide , Animais , Proliferação de Células , Histona-Lisina N-Metiltransferase , Humanos , Leucemia/patologia , Proteína de Leucina Linfoide-Mieloide/metabolismo , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Ratos , Fatores de Transcrição
4.
Chem Biol Interact ; 367: 110178, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36113632

RESUMO

Selenium is an essential trace element. High dosage of selenite exhibits a great potential in treating leukemia. Previous study discovered selenite could promote leukemia cells apoptosis through inducing DNA damage and cell cycle arrest, while the switch mechanisms of these events and autophagy were still unclear. Current study discovered selenite promoted autophagy and apoptosis of leukemia Jurkat cells. In this process, DNA damage related ATM/IKK alpha axis was activated. This axis could stabilize pro-apoptotic P73, and promote autophagy through regulating NF-kappaB signaling pathway. Moreover, survivin-2B was also confirmed to be necessary for the ATM-induced nuclear location of IKK alpha, and therefore stood at the node position of apoptosis and autophagy cascades inside Jurkat cells. Finally, our in vivo experiments proved that selenite exhibited some anti-tumor effects on Jurkat cells-bearing mice. Moreover, alterations of ATM and IKK alpha expression observed in vivo were similar to that identified in vitro. Therefore, our findings had fully confirmed survivin-2B dependent activation of ATM/IKK alpha axis might be another crosstalk between autophagy and apoptosis of selenite-treated leukemia cells.


Assuntos
Leucemia , Selênio , Oligoelementos , Animais , Apoptose , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Autofagia , Humanos , Quinase I-kappa B/metabolismo , Células Jurkat , Leucemia/patologia , Camundongos , NF-kappa B/metabolismo , Ácido Selenioso/metabolismo , Ácido Selenioso/farmacologia , Selênio/farmacologia , Survivina/metabolismo , Oligoelementos/metabolismo
5.
Nature ; 609(7925): 174-182, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36002574

RESUMO

The efficacy of adoptive T cell therapies for cancer treatment can be limited by suppressive signals from both extrinsic factors and intrinsic inhibitory checkpoints1,2. Targeted gene editing has the potential to overcome these limitations and enhance T cell therapeutic function3-10. Here we performed multiple genome-wide CRISPR knock-out screens under different immunosuppressive conditions to identify genes that can be targeted to prevent T cell dysfunction. These screens converged on RASA2, a RAS GTPase-activating protein (RasGAP) that we identify as a signalling checkpoint in human T cells, which is downregulated upon acute T cell receptor stimulation and can increase gradually with chronic antigen exposure. RASA2 ablation enhanced MAPK signalling and chimeric antigen receptor (CAR) T cell cytolytic activity in response to target antigen. Repeated tumour antigen stimulations in vitro revealed that RASA2-deficient T cells show increased activation, cytokine production and metabolic activity compared with control cells, and show a marked advantage in persistent cancer cell killing. RASA2-knockout CAR T cells had a competitive fitness advantage over control cells in the bone marrow in a mouse model of leukaemia. Ablation of RASA2 in multiple preclinical models of T cell receptor and CAR T cell therapies prolonged survival in mice xenografted with either liquid or solid tumours. Together, our findings highlight RASA2 as a promising target to enhance both persistence and effector function in T cell therapies for cancer treatment.


Assuntos
Antígenos de Neoplasias , Neoplasias , Linfócitos T , Proteínas Ativadoras de ras GTPase , Animais , Antígenos de Neoplasias/imunologia , Medula Óssea , Sistemas CRISPR-Cas , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Humanos , Imunoterapia Adotiva , Leucemia/imunologia , Leucemia/patologia , Leucemia/terapia , Camundongos , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Fatores de Tempo , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas Ativadoras de ras GTPase/deficiência , Proteínas Ativadoras de ras GTPase/genética
6.
Cell Rep Med ; 3(8): 100717, 2022 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-35977468

RESUMO

Leukemia cells re-program their microenvironment to augment blast proliferation and enhance treatment resistance. Means of clinically targeting such niche-driven treatment resistance remain ambiguous. We develop human induced pluripotent stem cell (hiPSC)-engineered niches to reveal druggable cancer-niche dependencies. We reveal that mesenchymal (iMSC) and vascular niche-like (iANG) hiPSC-derived cells support ex vivo proliferation of patient-derived leukemia cells, affect dormancy, and mediate treatment resistance. iMSCs protect dormant and cycling blasts against dexamethasone, while iANGs protect only dormant blasts. Leukemia proliferation and protection from dexamethasone-induced apoptosis is dependent on cancer-niche interactions mediated by CDH2. Consequently, we test CDH2 antagonist ADH-1 (previously in Phase I/II trials for solid tumors) in a very aggressive patient-derived xenograft leukemia mouse model. ADH-1 shows high in vivo efficacy; ADH-1/dexamethasone combination is superior to dexamethasone alone, with no ADH-1-conferred additional toxicity. These findings provide a proof-of-concept starting point to develop improved, potentially safer therapeutics targeting niche-mediated cancer dependencies in blood cancers.


Assuntos
Células-Tronco Pluripotentes Induzidas , Leucemia , Neoplasias , Animais , Medula Óssea/patologia , Dexametasona/farmacologia , Resistencia a Medicamentos Antineoplásicos , Humanos , Leucemia/patologia , Camundongos , Neoplasias/patologia , Microambiente Tumoral
7.
Int J Mol Sci ; 23(13)2022 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-35806354

RESUMO

Cellular senescence is recognized as a dynamic process in which cells evolve and adapt in a context dependent manner; consequently, senescent cells can exert both beneficial and deleterious effects on their surroundings. Specifically, senescent mesenchymal stromal cells (MSC) in the bone marrow (BM) have been linked to the generation of a supporting microenvironment that enhances malignant cell survival. However, the study of MSC's senescence role in leukemia development has been straitened not only by the availability of suitable models that faithfully reflect the structural complexity and biological diversity of the events triggered in the BM, but also by the lack of a universal, standardized method to measure senescence. Despite these constraints, two- and three dimensional in vitro models have been continuously improved in terms of cell culture techniques, support materials and analysis methods; in addition, research on animal models tends to focus on the development of techniques that allow tracking leukemic and senescent cells in the living organism, as well as to modify the available mice strains to generate individuals that mimic human BM characteristics. Here, we present the main advances in leukemic niche modeling, discussing advantages and limitations of the different systems, focusing on the contribution of senescent MSC to leukemia progression.


Assuntos
Leucemia , Células-Tronco Mesenquimais , Animais , Medula Óssea/patologia , Senescência Celular , Leucemia/patologia , Camundongos , Microambiente Tumoral
8.
Nat Med ; 28(7): 1439-1446, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35788175

RESUMO

Clonal hematopoiesis of indeterminate potential (CHIP) increases rapidly in prevalence beyond age 60 and has been associated with increased risk for malignancy, heart disease and ischemic stroke. CHIP is driven by somatic mutations in hematopoietic stem and progenitor cells (HSPCs). Because mutations in HSPCs often drive leukemia, we hypothesized that HSPC fitness substantially contributes to transformation from CHIP to leukemia. HSPC fitness is defined as the proliferative advantage over cells carrying no or only neutral mutations. If mutations in different genes lead to distinct fitness advantages, this could enable patient stratification. We quantified the fitness effects of mutations over 12 years in older age using longitudinal sequencing and developed a filtering method that considers individual mutational context alongside mutation co-occurrence to quantify the growth potential of variants within individuals. We found that gene-specific fitness differences can outweigh inter-individual variation and, therefore, could form the basis for personalized clinical management.


Assuntos
Hematopoese , Leucemia , Hematopoiese Clonal , Hematopoese/genética , Células-Tronco Hematopoéticas/patologia , Humanos , Leucemia/patologia , Pessoa de Meia-Idade , Mutação/genética
9.
Blood ; 140(11): 1200-1228, 2022 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-35767897

RESUMO

The classification of myeloid neoplasms and acute leukemias was last updated in 2016 within a collaboration between the World Health Organization (WHO), the Society for Hematopathology, and the European Association for Haematopathology. This collaboration was primarily based on input from a clinical advisory committees (CACs) composed of pathologists, hematologists, oncologists, geneticists, and bioinformaticians from around the world. The recent advances in our understanding of the biology of hematologic malignancies, the experience with the use of the 2016 WHO classification in clinical practice, and the results of clinical trials have indicated the need for further revising and updating the classification. As a continuation of this CAC-based process, the authors, a group with expertise in the clinical, pathologic, and genetic aspects of these disorders, developed the International Consensus Classification (ICC) of myeloid neoplasms and acute leukemias. Using a multiparameter approach, the main objective of the consensus process was the definition of real disease entities, including the introduction of new entities and refined criteria for existing diagnostic categories, based on accumulated data. The ICC is aimed at facilitating diagnosis and prognostication of these neoplasms, improving treatment of affected patients, and allowing the design of innovative clinical trials.


Assuntos
Neoplasias Hematológicas , Leucemia , Transtornos Mieloproliferativos , Doença Aguda , Consenso , Genômica , Neoplasias Hematológicas/patologia , Humanos , Leucemia/diagnóstico , Leucemia/genética , Leucemia/patologia , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/patologia , Organização Mundial da Saúde
10.
Adv Skin Wound Care ; 35(6): 1-4, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35703855

RESUMO

ABSTRACT: Pityriasis rubra pilaris (PRP) is a rare, chronic papulosquamous disorder that presents with scaling plaques, palmoplantar keratoderma, and keratotic follicular papules. Typically, there are distinctive unaffected areas referred to as "islands of sparing." Pityriasis rubra pilaris has been associated with various immunodeficient states and malignancies.The authors conducted a literature review using MEDLINE, PubMed, and Google Scholar, documenting all known cases of PRP associated with malignancy; 15 cases were found in the literature. They also present the case of a 49-year-old White man who, prior to referral to dermatology, was seen in urgent care for widespread pruritic rash. Physical examination in the dermatology clinic revealed confluent, scaly erythematous papules coalescing into plaques with island of sparing involving the trunk and upper and lower extremities. Bilateral palms and soles showed hyperkeratosis with fissuring. He was diagnosed with PRP after punch biopsy and began a new course of topical corticosteroid therapy. Hematology was consulted because of abnormal complete blood count results, and he was subsequently diagnosed with chronic lymphoid leukemia.Treatment of PRP is largely based on clinical experience and may involve corticosteroids, immunomodulators, or biologic therapy. The relationship between PRP and malignancy is unknown. Current theories postulate it may be driven by tumor production of functional peptides or antigen cross-reactivity between cancer cells and the skin. This is the second reported case of PRP as a manifestation of leukemia, and the first of chronic lymphoid leukemia. Although not yet understood, the documented relationship between PRP and malignancy prompts screening for cancer in all patients with new-onset PRP.


Assuntos
Leucemia Linfoide , Leucemia , Pitiríase Rubra Pilar , Biópsia , Humanos , Leucemia/complicações , Leucemia/patologia , Leucemia Linfoide/complicações , Leucemia Linfoide/patologia , Masculino , Pessoa de Meia-Idade , Pitiríase Rubra Pilar/diagnóstico , Pitiríase Rubra Pilar/tratamento farmacológico , Pitiríase Rubra Pilar/patologia , Pele/patologia
11.
Med Oncol ; 39(5): 65, 2022 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-35478057

RESUMO

Giant cells with polyploidy, termed polyploid giant cells, have been observed during normal growth, development, and pathologic states, such as solid cancer progression and resistance to therapy. Functional studies of polyploidal giant cancer cells (PGCC) provided evidence that they arise when normal diploid cells are stressed, show stem cell-like properties, and give rise to tumors. In the present study, we report in K562 leukemia cell line that introduction of the hotspot K700E mutation in the gene SF3B1 using CRISPR/Cas9 method results in an increased frequency of multinucleated polyploid giant cells resistant to chemotherapeutic agent and serum starvation stress. These giant cells with higher ploidy are distinct from multinucleated megakaryocytes, are proliferative, and are characterized by increased accumulation of mitochondria. PGCC have been previously documented in solid tumors. This is the first report describing PGCCs in a cell line derived from a liquid cancer where increased frequency of PGCCs is linked to a specific genetic event. Since SF3B1 mutations are predominantly seen in MDS and other hematologic malignancies, our current findings will have significant clinical implications.


Assuntos
Leucemia , Neoplasias , Células Gigantes/patologia , Humanos , Leucemia/patologia , Mutação , Neoplasias/patologia , Fosfoproteínas/metabolismo , Poliploidia , Fatores de Processamento de RNA/genética , Fatores de Processamento de RNA/metabolismo
12.
Oncologist ; 27(8): e661-e670, 2022 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-35472244

RESUMO

BACKGROUND: This review summarizes the case studies of PCM1-JAK2 fusion tyrosine kinase gene-related neoplasia. Recommended treatment includes JAK2 inhibitors and hematologic stem cell transplantation (HSCT), although the small number of patients has limited study of their efficacy. Herein, we present all available cases in the current searchable literature with their demographics, diagnoses, treatments, and outcomes. METHODS: PubMed, ScienceDirect, Publons, the Cochrane Library, and Google were searched with the following terms: PCM1-JAK2, ruxolitinib and myeloid/lymphoid. RESULTS: Sixty-six patients (mean age = 50, 77% male) had an initial diagnosis of myeloproliferative neoplasm (MPN) in 40, acute leukemia in 21 and T-cell cutaneous lymphoma in 5. Thirty-five patients (53%) had completed 5-year follow-up. The 5-year survival for the MPN, acute myelogenous leukemia (AML), acute lymphocytic leukemia, and lymphoma groups are 62.7, 14.9%, 40.0%, and 100%, respectively. Too few patients have been treated with ruxolitinib to draw conclusions regarding its effect on survival while the 5-year survival for MPN patients with or without HSCT was 80.2% (40.3%-94.8%) versus 51.5% (22.3%-74.6%), respectively. The T-cell cutaneous lymphoma patients have all survived at least 7 years. CONCLUSION: This rare condition may be increasingly detected with wider use of genomics. Ruxolitinib can yield hematologic and molecular remissions. However, HSCT is, at this time, the only potentially curative treatment. Useful prognostic markers are needed to determine appropriate timing for HSCT in patients with MPN. Patients presenting with acute leukemia have a poor prognosis.


Assuntos
Leucemia , Linfoma , Transtornos Mieloproliferativos , Feminino , Humanos , Janus Quinase 2/genética , Leucemia/patologia , Masculino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/terapia , Proteínas de Fusão Oncogênica
13.
Epigenetics ; 17(12): 1715-1725, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35412430

RESUMO

Aberrantly methylated genes contribute to the landscape of epigenetic alterations in colorectal adenocarcinoma. The global CpG Island methylator phenotype (CIMP) and individually methylated genes are potential prognostic/predictive biomarkers. Research suggests an association between methylated DCR1 (mDCR1) and lack of benefit with irinotecan (IFL) treatment. We assessed the association between DCR1 methylation status and survival in patients receiving adjuvant fluorouracil/ leucovorin (5-FU/LV) or IFL. We analysed data from patients with stage III colon adenocarcinoma randomly assigned to adjuvant 5-FU/LV or IFL in CALGB 89803 (Alliance). The primary endpoint was overall survival (OS), and the secondary endpoint was disease-free survival (DFS). Using tumour sample DNA, we evaluated the association between survival, DCR1 methylation status, and molecular subgroups (BRAF, KRAS, mismatch repair status, CIMP status) using Kaplan-Meier estimator and Cox proportional hazard model. mDCR1 was observed in 221/400 (55%) colon cancers. Histopathologic features were similar between mDCR1 and unmethylated DCR1 (unDCR1) colon cancers. There was no difference in OS (p = 0.83) or DFS (p = 0.85) based on DCR1 methylation status. There was no association between methylation status and response to IFL . In patients with unDCR1 and KRAS-wildtype tumours, those who received IFL had a nearly two-fold worse DFS compared to patients who received 5-FU/LV (HR = 1.85, 95% CI (0.97-3.53, p = 0.06). This relationship was not notable among other subgroups. In stage III colon cancer patients, mDCR1 status did not associate with response to irinotecan. Larger studies may suggest an association between the iridocene response and molecular subgroups.


Assuntos
Adenocarcinoma , Neoplasias do Colo , Leucemia , Humanos , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores , Quimioterapia Adjuvante , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Intervalo Livre de Doença , Metilação de DNA , Fluoruracila/uso terapêutico , Irinotecano/uso terapêutico , Leucovorina/uso terapêutico , Leucemia/genética , Leucemia/patologia , Estadiamento de Neoplasias , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética
14.
Methods Mol Biol ; 2419: 73-88, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35237959

RESUMO

Outgrowth of a mutated hematopoietic stem/progenitor clone and its descendants, also known as clonal hematopoiesis, has long been considered as either a potential forerunner to hematologic malignancy or as a clinically silent phase in leukemia that antedates symptomatic disease. That definition of clonal hematopoiesis has now been expanded to encompass patients who harbor specific genetic/epigenetic mutations that lead to clonal hematopoiesis of indeterminate potential (CHIP) and, with it, a relatively heightened risk for both myeloid malignancy and atherosclerosis during aging. In this review, we provide contemporary insights into the cellular and molecular basis for CHIP and explore the relationship of CHIP to myeloid malignancy and atherosclerosis. We also discuss emerging strategies to explore CHIP biology and clinical targeting of CHIP related malignancy and cardiovascular disease.


Assuntos
Aterosclerose , Leucemia , Neoplasias , Aterosclerose/genética , Aterosclerose/patologia , Hematopoiese Clonal/genética , Hematopoese/genética , Células-Tronco Hematopoéticas/patologia , Humanos , Leucemia/patologia , Mutação , Neoplasias/genética
15.
Acta Gastroenterol Belg ; 85(1): 118-119, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35305008

RESUMO

A woman, followed for chronic myeloid leukaemia, presented for a routine examination. Her medical history was marked by recurrent Helicobacter pylori gastritis and polymyalgica rheumatica. She was under dasatinib and hormone replacement therapy. At clinical examination, she complained about digestive disorders with altered bowel habits. Biology, including leucocyte count, remained normal. A colonoscopy was performed. Endoscopic examination revealed a colonic mucosa covered by multiple tiny nodular lesions (<5mm) from the hepatic angle to the sigmoid and with an abnormal pattern of vascularisation (Fig. 1). Staged biopsies were taken. Microscopic examination revealed discrete achi-tectural distortions. The stroma contained a mixed inflammatory infiltrate composed of neutrophils, eosinophils and lymphocytes. Immunohistochemistry for CD3, CD5, CD20 and CD79 did not bring arguments for a lymphoma. There were no malignant or dysplastic cells. (Fig. 2). What is your diagnosis?


Assuntos
Leucemia , Pólipos , Colo/patologia , Colonoscopia , Feminino , Humanos , Mucosa Intestinal/patologia , Leucemia/patologia , Pólipos/patologia
16.
J Enzyme Inhib Med Chem ; 37(1): 895-911, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35345960

RESUMO

A novel series of 4-(4-Methoxyphenyl)-2-(methylthio)pyrimidine-5-carbonitrile was developed linked to an aromatic moiety via N-containing bridge and then evaluated for their cytotoxic activity against MCF-7 and K562 cell lines. Seven compounds exhibited the highest activity against both cell lines where compounds 4d and 7f were the most active against K562 cell line. Exploring their molecular mechanisms by enzyme inhibition assay on PI3Kδ/γ and AKT-1 showed that compound 7f was promising more than 4d with IC50 = 6.99 ± 0.36, 4.01 ± 0.55, and 3.36 ± 0.17 uM, respectively. Also, flowcytometric analysis revealed that 7f caused cell cycle arrest at S-phase followed by caspase 3 dependent apoptosis induction. Mechanistically, compound 7f proved to modulate the expression of PI3K, p-PI3K, AKT, p-AKT, Cyclin D1, and NFΚß. Furthermore, in-vivo toxicity study indicated good safety profile for 7f. These findings suggest that the trimethoxy derivative 7f has strong potential as a multi-acting inhibitor on PI3K/AKT axis targeting breast cancer and leukaemia.


Assuntos
Antineoplásicos , Leucemia , Nitrilas , Pirimidinas , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Caspase 3 , Ciclina D1 , Humanos , Células K562 , Leucemia/tratamento farmacológico , Leucemia/patologia , Células MCF-7 , NF-kappa B , Nitrilas/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/farmacologia , Pirimidinas/farmacologia
17.
Stem Cell Rev Rep ; 18(6): 2179-2194, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35188601

RESUMO

BACKGROUND: The heterogeneity of mitochondrial function is an important feature of hematopoietic cell lineage differentiation, but its stage wise contribution is not adequately studied. To establish a model to compare the lineage differentiation of hematopoietic stem cells (HSCs), hematopoietic progenitor cells (HPCs), and differentiated blood cells, the mitochondrial mass (MM), mitochondrial membrane potential (MMP), reactive oxygen species (ROS), and mitophagy level were analyzed. RESULTS AND DISCUSSION: HSCs had lower mitochondrial metabolic activity than committed progenitor populations, indicated by lower MM, MMP, and ROS and higher mitophagy. HPC1s shared more stem cell characteristics than HPC2s and committed progenitor populations in terms of mitochondrial number and function. The mitochondrial metabolism of mature blood cells had greater heterogeneity than hematopoietic stem and progenitor cells, with granulocytes being similar to monocytes. Moreover, HSCs exhibited heterogeneity in the selection of mitophagy-related PINK1/PARK2, BNIP3/NIX, and FUNDC1 pathways. Myeloid differentiation had greater morphological and functional heterogeneity of hematopoietic cells than lymphoid differentiation. Additionally, leukemia stem cells had higher aerobic metabolism and better stem cell function through elevated mitophagy than normal hematopoietic cells. ROS and MMP levels in differentiated leukemia cells were higher, but the level of mitophagy was lower than in differentiated hematopoietic cells. CONCLUSION: This study provides a complete set of methods and basic reference values for the systematic study of the mitochondrial metabolic function of different types of hematopoietic cells under physiological and pathological conditions. The findings contribute to the future research of tumor and aging based on mitochondrial metabolism.


Assuntos
Leucemia , Mitofagia , Células-Tronco Hematopoéticas , Humanos , Leucemia/patologia , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo
18.
Int J Mol Sci ; 23(4)2022 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-35216407

RESUMO

Self-maintaining hematopoietic stem cells are a cell population that is primarily 'at risk' to malignant transformation, and the cell-of-origin for some leukemias. Tissue-specific stem cells replenish the different types of functional cells within a particular tissue to meet the demands of an organism. For hematopoietic stem cells, this flexibility is important to satisfy the changing requirements for a certain type of immune cell, when needed. From studies of the natural history of childhood acute lymphoblastic leukemia, an initial oncogenic and prenatal insult gives rise to a preleukemic clone. At least a second genomic insult is needed that gives rise to a leukemia stem cell: this cell generates a hierarchy of leukemia cells. For some leukemias, there is evidence to support the concept that one of the genomic insults leads to dysregulation of the tissue homeostatic role of hematopoietic stem cells so that the hierarchy of differentiating leukemia cells belongs to just one cell lineage. Restricting the expression of particular oncogenes in transgenic mice to hematopoietic stem and progenitor cells led to different human-like lineage-restricted leukemias. Lineage restriction is seen for human leukemias by virtue of their sub-grouping with regard to a phenotypic relationship to just one cell lineage.


Assuntos
Leucemia/genética , Oncogenes/genética , Animais , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Células-Tronco Hematopoéticas/patologia , Humanos , Leucemia/patologia
19.
Cell Rep ; 38(7): 110369, 2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-35172132

RESUMO

DOT1L methylates histone H3 lysine 79 during transcriptional elongation and is stimulated by ubiquitylation of histone H2B lysine 120 (H2BK120ub) in a classical trans-histone crosstalk pathway. Aberrant genomic localization of DOT1L is implicated in mixed lineage leukemia (MLL)-rearranged leukemias, an aggressive subset of leukemias that lacks effective targeted treatments. Despite recent atomic structures of DOT1L in complex with H2BK120ub nucleosomes, fundamental questions remain as to how DOT1L-ubiquitin and DOT1L-nucleosome acidic patch interactions observed in these structures contribute to nucleosome binding and methylation by DOT1L. Here, we combine bulk and single-molecule biophysical measurements with cancer cell biology to show that ubiquitin and cofactor binding drive conformational changes to stimulate DOT1L activity. Using structure-guided mutations, we demonstrate that ubiquitin and nucleosome acidic patch binding by DOT1L are required for cell proliferation in the MV4; 11 leukemia model, providing proof of principle for MLL targeted therapeutic strategies.


Assuntos
Histona-Lisina N-Metiltransferase/metabolismo , Leucemia/metabolismo , Nucleossomos/metabolismo , Ubiquitinação , Linhagem Celular Tumoral , Proliferação de Células , Rearranjo Gênico , Histona-Lisina N-Metiltransferase/química , Histona-Lisina N-Metiltransferase/genética , Histonas/metabolismo , Humanos , Leucemia/patologia , Lisina/metabolismo , Masculino , Metilação , Modelos Moleculares , Proteína de Leucina Linfoide-Mieloide/genética , Ligação Proteica , Ubiquitina/metabolismo
20.
Cells ; 11(3)2022 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-35159389

RESUMO

Myelodysplastic syndromes (MDS) are myeloid neoplasms characterized by bone marrow dysfunction and increased risk of transformation to leukemia. MDS represent complex and diverse diseases that evolve from malignant hematopoietic stem cells and involve not only the proliferation of malignant cells but also the dysfunction of normal bone marrow. Specifically, the marrow microenvironment-both hematopoietic and stromal components-is disrupted in MDS. While microenvironmental disruption has been described in human MDS and murine models of the disease, only a few current treatments target the microenvironment, including the immune system. In this review, we will examine current evidence supporting three key interdependent pillars of microenvironmental alteration in MDS-immune dysfunction, cytokine skewing, and stromal changes. Understanding the molecular changes seen in these diseases has been, and will continue to be, foundational to developing effective novel treatments that prevent disease progression and transformation to leukemia.


Assuntos
Doenças do Sistema Imunitário , Leucemia , Síndromes Mielodisplásicas , Animais , Medula Óssea/patologia , Citocinas , Células-Tronco Hematopoéticas/patologia , Humanos , Leucemia/patologia , Camundongos , Síndromes Mielodisplásicas/patologia , Microambiente Tumoral
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