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1.
Exp Hematol ; : 104255, 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38876252

RESUMO

The genetic lesions that drive acute megakaryoblastic leukemia (AMKL) have not been fully elucidated. To search for genetic alterations in AMKL, we performed targeted deep sequencing in 34 AMKL patient samples and 8 AMKL cell lines and detected frequent genetic mutations in the NOTCH pathway in addition to previously reported alterations in GATA-1 and the JAK-STAT pathway. Pharmacological and genetic NOTCH activation, but not inhibition, significantly suppressed AMKL cell proliferation in both in vitro and in vivo assays employing a patient-derived xenograft model. These results suggest that NOTCH inactivation underlies AMKL leukemogenesis. and NOTCH activation holds the potential for therapeutic application in AMKL.

2.
iScience ; 25(10): 105194, 2022 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-36217548

RESUMO

We reported earlier that IQGAP3 is an important stem cell factor in rapidly proliferating isthmus stem cells in the stomach and that IQGAP3 expression is robustly induced in terminally differentiated chief cells and de-differentiated cells following tissue damage. The elevated IQGAP3 expression in cancer and its association with metastasis suggest a fundamental role for IQGAP3 in proliferating cancer stem cells. What causes IQGAP3 upregulation in cancer is unclear. Here, we show that IGF2BP1 and IQGAP3 expression levels are highest in the blastocyst, with both decreasing during adulthood. This suggests that IQGAP3, like IGF2BP1, is an early developmental gene that is aberrantly upregulated upon re-expression of IGF2BP1 during carcinogenesis. IGF2BP1 binds and stabilizes m6A-modified IQGAP3 transcripts. Downstream targets of IGF2BP1, namely SRF and FOXM1, also upregulate IQGAP3 expression. These multiple layers of IQGAP3 regulation, which may safeguard against inappropriate stem cell proliferation, present additional drug targets to inhibit IQGAP3-driven malignant growth.

3.
J Fungi (Basel) ; 7(8)2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34436195

RESUMO

The existence of a hyperinflammatory state has been observed in patients with invasive fungal infections (IFI). It is being postulated whether morbidity from IFI may, in part, be a consequence of an unnecessarily prolonged or exaggerated proinflammatory immune response including interleukin 6 (IL-6) post-infection, in a host with dysregulated or compromised immunity. This, in turn, induces collateral host injury at the tissue and organ level, leading to adverse outcomes. Tocilizumab has become widely used as an immunomodulator in the treatment of inflammatory conditions. Here, we evaluated the use of tocilizumab to curb post-infective inflammatory flare in the setting of an in-vivo mouse model for invasive candidiasis. Following Candida infection, the tocilizumab-treated mice showed improved short-term survival compared with the saline-treated control mice. There was a reduced inflammatory response mounted by the host, coupled with reduced IL-6 but increased IL-10 levels. TNF-α and IFN-γ responses were not affected. Tocilizumab facilitated immune tolerance by selectively inducing IL-10, producing CD8α+ conventional dendritic cells (DCs) and peripheral T-regulatory cells, over CD11b+ conventional DCs and plasmacytoid DCs. We demonstrate here the sequelae from immunomodulatory manipulation and the basis whereby the use of monoclonal antibodies may be further explored in IFI.

5.
Gene ; 774: 145421, 2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33444684

RESUMO

Epstein-Barr virus nuclear antigens 2 (EBNA2) mediated super-enhancers, defined by in silico data, localize near genes associated with B cell transcription factors including RUNX3. However, the biological function of super-enhancer for RUNX3 gene (seR3) remains unclear. Here, we show that two seR3s, tandemly-located at 59- and 70-kb upstream of RUNX3 transcription start site, named seR3 -59h and seR3 -70h, are required for RUNX3 expression and cell proliferation in Epstein-Barr virus (EBV)-positive malignant B cells. A BET bromodomain inhibitor, JQ1, potently suppressed EBV-positive B cell growth through the reduction of RUNX3 and MYC expression. Excision of either or both seR3s by employing CRISPR/Cas9 system resulted in the decrease in RUNX3 expression and the subsequent suppression of cell proliferation and colony forming capability. The expression of MYC was also reduced when seR3s were deleted, probably due to the loss of trans effect of seR3s on the super-enhancers for MYC. These findings suggest that seR3s play a pivotal role in expression and biological function of both RUNX3 and MYC. seR3s would serve as a potential therapeutic target in EBV-related widespread tumors.


Assuntos
Linfócitos B/virologia , Proliferação de Células/genética , Subunidade alfa 3 de Fator de Ligação ao Core/genética , Elementos Facilitadores Genéticos , Herpesvirus Humano 4/fisiologia , Azepinas/farmacologia , Linfócitos B/citologia , Linfoma de Burkitt/genética , Linfoma de Burkitt/virologia , Sistemas CRISPR-Cas , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Fase G1/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Genes myc , Humanos , Domínios Proteicos , Proteínas/antagonistas & inibidores , Proteínas/metabolismo , Triazóis/farmacologia
6.
Nat Commun ; 10(1): 5349, 2019 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-31836706

RESUMO

Increased levels and non-telomeric roles have been reported for shelterin proteins, including RAP1 in cancers. Herein using Rap1 null mice, we provide the genetic evidence that mammalian Rap1 plays a major role in hematopoietic stem cell survival, oncogenesis and response to chemotherapy. Strikingly, this function of RAP1 is independent of its association with the telomere or with its known partner TRF2. We show that RAP1 interacts with many members of the DNA damage response (DDR) pathway. RAP1 depleted cells show reduced interaction between XRCC4/DNA Ligase IV and DNA-PK, and are impaired in DNA Ligase IV recruitment to damaged chromatin for efficient repair. Consistent with its role in DNA damage repair, RAP1 loss decreases double-strand break repair via NHEJ in vivo, and consequently reduces B cell class switch recombination. Finally, we discover that RAP1 levels are predictive of the success of chemotherapy in breast and colon cancer.


Assuntos
Antineoplásicos/farmacologia , Carcinogênese/metabolismo , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Proteínas de Ligação a Telômeros/metabolismo , Proteínas rap1 de Ligação ao GTP/metabolismo , Animais , Carcinogênese/efeitos dos fármacos , Carcinogênese/patologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Dano ao DNA , DNA Ligase Dependente de ATP/metabolismo , Reparo do DNA/efeitos dos fármacos , Reparo do DNA/efeitos da radiação , Proteína Quinase Ativada por DNA/metabolismo , Fluoruracila/farmacologia , Raios gama , Instabilidade Genômica/efeitos dos fármacos , Instabilidade Genômica/efeitos da radiação , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/efeitos da radiação , Humanos , Camundongos Knockout , Mutagênicos/toxicidade , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/efeitos da radiação , Proteínas Proto-Oncogênicas c-myc/metabolismo , Complexo Shelterina , Análise de Sobrevida
7.
Biomark Res ; 6: 16, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29780592

RESUMO

BACKGROUND: Germline mutations in the RUNX1 transcription factor give rise to a rare autosomal dominant genetic condition classified under the entity: Familial Platelet Disorders with predisposition to Acute Myeloid Leukaemia (FPD/AML). While several studies have identified a myriad of germline RUNX1 mutations implicated in this disorder, second-hit mutational events are necessary for patients with hereditary thrombocytopenia to develop full-blown AML. The molecular picture behind this process remains unclear. We describe a patient of Malay descent with an unreported 7-bp germline RUNX1 frameshift deletion, who developed second-hit mutations that could have brought about the leukaemic transformation from a pre-leukaemic state. These mutations were charted through the course of the treatment and stem cell transplant, showing a clear correlation between her clinical presentation and the mutations present. CASE PRESENTATION: The patient was a 27-year-old Malay woman who presented with AML on the background of hereditary thrombocytopenia affecting her father and 3 brothers. Initial molecular testing revealed the same novel RUNX1 mutation in all 5 individuals. The patient received standard induction, consolidation chemotherapy, and a haploidentical stem cell transplant from her mother with normal RUNX1 profile. Comprehensive genomic analyses were performed at diagnosis, post-chemotherapy and post-transplant. A total of 8 mutations (RUNX1, GATA2, DNMT3A, BCORL1, BCOR, 2 PHF6 and CDKN2A) were identified in the pre-induction sample, of which 5 remained (RUNX1, DNMT3A, BCORL1, BCOR and 1 out of 2 PHF6) in the post-treatment sample and none were present post-transplant. In brief, the 3 mutations which were lost along with the leukemic cells at complete morphological remission were most likely acquired leukemic driver mutations that were responsible for the AML transformation from a pre-leukemic germline RUNX1-mutated state. On the contrary, the 5 mutations that persisted post-treatment, including the germline RUNX1 mutation, were likely to be part of the preleukemic clone. CONCLUSION: Further studies are necessary to assess the prevalence of these preleukemic and secondary mutations in the larger FPD/AML patient cohort and establish their prognostic significance. Given the molecular heterogeneity of FPD/AML and other AML subtypes, a better understanding of mutational classes and their involvement in AML pathogenesis can improve risk stratification of patients for more effective and targeted therapy.

8.
Adv Exp Med Biol ; 962: 117-138, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28299655

RESUMO

The Runx family genes play important roles in development and cancer, largely via their regulation of tissue stem cell behavior. Their involvement in two organs, blood and skin, is well documented. This review summarizes currently known Runx functions in the stem cells of these tissues. The fundamental core mechanism(s) mediated by Runx proteins has been sought; however, it appears that there does not exist one single common machinery that governs both tissue stem cells. Instead, Runx family genes employ multiple spatiotemporal mechanisms in regulating individual tissue stem cell populations. Such specific Runx requirements have been unveiled by a series of cell type-, developmental stage- or age-specific gene targeting studies in mice. Observations from these experiments revealed that the regulation of stem cells by Runx family genes turned out to be far more complex than previously thought. For instance, although it has been reported that Runx1 is required for the endothelial-to-hematopoietic cell transition (EHT) but not thereafter, recent studies clearly demonstrated that Runx1 is also needed during the period subsequent to EHT, namely at perinatal stage. In addition, Runx1 ablation in the embryonic skin mesenchyme eventually leads to complete loss of hair follicle stem cells (HFSCs) in the adult epithelium, suggesting that Runx1 facilitates the specification of skin epithelial stem cells in a cell extrinsic manner. Further in-depth investigation into how Runx family genes are involved in stem cell regulation is warranted.


Assuntos
Subunidades alfa de Fatores de Ligação ao Core/genética , Subunidades alfa de Fatores de Ligação ao Core/metabolismo , Células-Tronco/metabolismo , Células-Tronco/fisiologia , Animais , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Epitélio/metabolismo , Folículo Piloso/metabolismo , Folículo Piloso/fisiologia , Humanos , Pele/metabolismo , Pele/fisiopatologia
9.
Gene ; 545(1): 111-6, 2014 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-24792891

RESUMO

The RUNX1/AML1 gene is among the most frequently mutated genes in human leukaemia. However, its association with T-cell acute lymphoblastic leukaemia (T-ALL) remains poorly understood. In order to examine RUNX1 point mutations in T-ALL, we conducted an amplicon-based deep sequencing in 65 Southeast Asian childhood patients and 20 T-ALL cell lines, and detected RUNX1 mutations in 6 patients (9.2%) and 5 cell lines (25%). Interestingly, RUNX1-mutated T-ALL cases seem to constitute a subset of early immature T-ALL that may originate from differentiated T-cells. This result provides a deeper insight into the mechanistic basis for leukaemogenesis.


Assuntos
Diferenciação Celular/genética , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Mutação Puntual , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Adolescente , Linhagem Celular Tumoral , Criança , Pré-Escolar , Feminino , Genes Codificadores da Cadeia gama de Receptores de Linfócitos T , Humanos , Masculino , Deleção de Sequência , Adulto Jovem
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