RESUMO
ABSTRACT: Hematopoietic differentiation is controlled by intrinsic regulators and the extrinsic hematopoietic niche. Activating transcription factor 4 (ATF4) plays a crucial role in the function of fetal and adult hematopoietic stem cell maintenance. However, the precise function of ATF4 in the bone marrow (BM) niche and the mechanism by which ATF4 regulates adult hematopoiesis remain largely unknown. Here, we used 4 cell-type-specific mouse Cre lines to achieve conditional knockout of Atf4 in Cdh5+ endothelial cells, Prx1+ BM stromal cells, Osx+ osteoprogenitor cells, and Mx1+ hematopoietic cells and uncovered the role of Atf4 in niche cells and hematopoiesis. Intriguingly, depletion of Atf4 in niche cells did not affect hematopoiesis; however, Atf4-deficient hematopoietic cells exhibited erythroid differentiation defects, leading to hypoplastic anemia. Mechanistically, ATF4 mediated direct regulation of Rps19bp1 transcription, which is, in turn, involved in 40 S ribosomal subunit assembly to coordinate ribosome biogenesis and promote erythropoiesis. Finally, we demonstrate that under conditions of 5-fluorouracil-induced stress, Atf4 depletion impedes the recovery of hematopoietic lineages, which requires efficient ribosome biogenesis. Taken together, our findings highlight the indispensable role of the ATF4-RPS19BP1 axis in the regulation of erythropoiesis.
Assuntos
Fator 4 Ativador da Transcrição , Eritropoese , Ribossomos , Animais , Fator 4 Ativador da Transcrição/metabolismo , Fator 4 Ativador da Transcrição/genética , Camundongos , Ribossomos/metabolismo , Proteínas Ribossômicas/metabolismo , Proteínas Ribossômicas/genética , Camundongos Knockout , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/citologiaRESUMO
Macrophages, critical components of bone marrow microenvironment, are reported to be remodeled into leukemia-associated macrophages (LAMs) in leukemic microenvironment where they contribute to leukemia development, characterized as M2 macrophages with pro-tumor effects. However, how leukemic microenvironment transforms macrophages into LAMs remains unknown. Here, we analyzed the clinical relevance of LAMs and profiled their RNA-Seq from acute myeloid leukemia (AML) patients with complete remission (CR) after induction treatment and refractory AML patients. Our results showed that the proportion and number of LAMs in refractory AML patients was higher than that in CR patients and LAM was a poor prognostic factor of AML patients. Furthermore, let-7b was a potentially aberrant gene in LAMs contributed to M2-subtype characteristics. Knockdown of let-7b in LAMs could inhibit the development of AML by repolarizing LAMs toward M1-subtype characteristics through the activation of Toll-like receptor and NF-κB pathway. Our study provides insight for future LAM-based immunotherapy strategies for AML.
Assuntos
Leucemia Mieloide Aguda , Humanos , Medula Óssea/patologia , Leucemia Mieloide Aguda/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Indução de Remissão , Microambiente Tumoral , MicroRNAs/genéticaRESUMO
Bone marrow mesenchymal stromal cells (BM-MSCs) are implicated in the pathogenesis of acute myeloid leukaemia (AML). However, due to the high heterogeneity of AML the mechanism underlying the cross-talk between MSCs and leukaemia cells is not well understood. We found that mixed-lineage leukaemia-AF9 (MLL-AF9)-induced AML mice-derived MSCs had higher proliferative viability compared to wild-type mice-derived MSCs with ubiquitin-conjugating enzyme E2O (Ube2o) down-regulation. After overexpression of UBE2O in AML-derived MSCs, the growth capacity of MSCs was reduced with nuclear factor kappa B subunit 1 (NF-κB) pathway deactivation. In vitro co-culture assay revealed that UBE2O-overexpression MSCs suppressed the proliferation and promoted apoptosis of AML cells by direct contact. In vivo results revealed that the leukaemia burden was reduced and the overall survival of AML mice was prolonged, with decreased dissemination of leukaemia cells in BM, spleen, liver and peripheral blood. Additionally, subcutaneous tumorigenesis revealed that tumour growth was also suppressed in the UBE2O-overexpression MSCs group. In conclusion, UBE2O was expressed at a low level in MLL-AF9-induced AML mice-derived MSCs. Overexpression of UBE2O in MSCs suppressed their proliferation through NF-κB pathway deactivation, which resulted in AML suppression. Our study provides a theoretical basis for a BM microenvironment-based therapeutic strategy to control disease progression.
Assuntos
Leucemia Mieloide Aguda , Células-Tronco Mesenquimais , Enzimas de Conjugação de Ubiquitina , Animais , Camundongos , Medula Óssea/patologia , Células da Medula Óssea/patologia , Leucemia Mieloide Aguda/patologia , Células-Tronco Mesenquimais/metabolismo , NF-kappa B/metabolismo , Microambiente Tumoral , Enzimas de Conjugação de Ubiquitina/genética , Enzimas de Conjugação de Ubiquitina/metabolismoRESUMO
The development of acute lymphoblastic leuakemia (ALL) is partly attributed to the effects of bone marrow (BM) microenvironment, especially mesenchymal stromal cells (MSCs), which interact bilaterally with leukaemia cells, leading to ALL progression. In order to find MSCs-based microenvironment targeted therapeutic strategies, Notch1-induced T-cell ALL (T-ALL) mice models were used and dynamic alterations of BM-MSCs with increased cell viability during T-ALL development was observed. In T-ALL mice derived stroma-based condition, leukaemia cells showed significantly elevated growth capacity indicating that MSCs participated in leukaemic niche formation. RNA sequence results revealed that T-ALL derived MSCs secreted fibroblast growth factor 2 (FGF2), which combined with fibroblast growth factor receptor 2 (FGFR2) on leukaemia cells, resulting in activation of PI3K/AKT/mTOR signalling pathway in leukaemia cells. In vitro blocking the interaction between FGF2 and FGFR2 with BGJ398 (infigratinib), a FGFR1-3 kinase inhibitor, or knockdown FGF2 in MSCs by interference caused deactivation of PI3K/AKT/mTOR pathway and dysregulations of genes associated with cell cycle and apoptosis in ALL cells, leading to decrease of leukaemia cells. In mouse model received BGJ398, overall survival was extended and dissemination of leukaemia cells in BM, spleen, liver and peripheral blood was decreased. After subcutaneous injection of primary human T-ALL cells with MSCs, tumour growth was suppressed when FGF2/FGFR2 was interrupted. Thus, inhibition of FGF2/FGFR2 interaction appears to be a valid strategy to overcome BM-MSCs mediated progression of T-ALL, and BGJ398 could indeed improve outcomes in T-ALL, which provide theoretical basis of BGJ398 as a BM microenvironment based therapeutic strategy to control disease progression.
Assuntos
Células-Tronco Mesenquimais , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Humanos , Camundongos , Animais , Fator 2 de Crescimento de Fibroblastos/farmacologia , Fator 2 de Crescimento de Fibroblastos/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Medula Óssea/metabolismo , Células-Tronco Mesenquimais/metabolismo , Células da Medula Óssea/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Microambiente TumoralRESUMO
Epstein-Barr virus (EBV) infection is proved to be associated with clinicopathology of lymphoma. However, little is known about the relationship between EBV-DNA status after treatment and prognosis. In this study, real-time polymerase chain reaction (PCR) was used for quantitative detection of EBV-DNA load in peripheral blood of all 26,527 patients with lymphoma, and the clinical characteristics and prognosis of 202 patients were retrospectively analysed, including 100 patients with positive EBV-DNA and 102 randomly selected patients with negative EBV-DNA. We found that the average rate of EBV-DNA positivity in lymphomas was 0.376%, and EBV-DNA-positive patients presented higher risk with elevated lactate dehydrogenase (LDH) and ß2-MG level, B symptoms, secondary hemophagocytic syndrome and lower objective response rate compared to EBV-DNA-negative patients. Multivariate analysis revealed EBV-DNA-positive patients had inferior progression-free survival (PFS) and overall survival (OS) and EBV-DNA level before treatment was related to PFS but not OS of T/NK cell lymphoma. In T/NK cell lymphoma, EBV-DNA converting negative after treatment was correlated with better PFS but not OS, and second-line therapy could induce more EBV-DNA-negative conversion compared to CHOP-based therapy. In all, EBV-DNA positivity before treatment can be a biomarker representing the tumour burden and an independent prognostic factor. EBV-DNA-negative conversion after treatment is a good prognostic factor for T/NK cell lymphomas.
Assuntos
Infecções por Vírus Epstein-Barr , Linfoma Extranodal de Células T-NK , Biomarcadores , DNA Viral/genética , Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4/genética , Humanos , Lactato Desidrogenases , Estudos RetrospectivosRESUMO
Acute lymphoblastic leukemia (ALL) is a kind of the most common hematopoietic malignancy, its recurrence and drug resistance are closely related to the bone marrow microenvironment. Bone marrow stromal cell (BMSC) is an important part of the bone marrow microenvironment and their interaction with leukemia cells cannot be ignored. BMSC participates in and regulate signaling pathways related to proliferation or apoptosis of ALL cells by secretes cytokines or extracellular matrix proteins, thus affecting the survival of ALL cells. In this review, the research advance of several signaling pathways of the interaction between BMSC and ALL cells was summarized briefly.
Assuntos
Células-Tronco Mesenquimais , Leucemia-Linfoma Linfoblástico de Células Precursoras , Apoptose , Medula Óssea , Células da Medula Óssea , Humanos , Células Estromais , Microambiente TumoralRESUMO
Triple-hit lymphoma (THL), which is classified into high-grade B-cell lymphoma with rearrangements of MYC, BCL2 and BCL6, presents aggressive biological behaviour. High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HSCT) is considered to be one of the recommended treatment options. Here, we reported 3 THL patients received carmustine, etoposide, cytarabine and cyclophosphamide (BEAC) combined with chidamide and high-dose rituximab conditioning regimen and found that this conditioning showed good efficacy and tolerance without increase of adverse events.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Linfoma/diagnóstico , Linfoma/terapia , Condicionamento Pré-Transplante , Aminopiridinas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzamidas/administração & dosagem , Biomarcadores Tumorais , Biópsia , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Linfoma/etiologia , Masculino , Pessoa de Meia-Idade , Mutação , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Rituximab/administração & dosagem , Tomografia Computadorizada por Raios X , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodos , Transplante Autólogo , Resultado do TratamentoRESUMO
Bone marrow (BM) microenvironment regulates and supports the production of blood cells which are necessary to maintain homeostasis. In analogy to normal hematopoiesis, leukemogenesis is originated from leukemic stem cells (LSCs) which gives rise to more differentiated malignant cells. Leukemia cells occupy BM niches and reconstruct them to support leukemogenesis. The abnormal BM niches are the main sanctuary of LSCs where they can evade chemotherapy-induced death and acquire drug resistance. In this review, we focus on the protective effects of BM niche cells on acute lymphoblastic leukemia cells.