Torque Teno Mini Virus as a cause of childhood acute promyelocytic leukemia lacking PML/RARA fusion
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE169521 | GEO | 2021/12/01
REPOSITORIES: GEO
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Project description:The aim of this study was to gain insight into the potential mechanism of resistance to arsenic trioxide (ATO). The gene expression profile of naive (NB4) (Acute promyelocytic leukemia (APL) cell line and one of its in house generated ATO resistant sub clone (NB4-VM-AsR1) was done using whole genome microarray and compared to generate the differential expression profile which will give insight into the mechanisms of ATO resistance in APL. Agilent one-color experiment,Organism: Human ,Agilent Whole Genome Human 4x44k (AMADID: 014850) , Labeling kit: Agilent Quick-Amp labeling Kit (p/n5190-0442) naive versus arsenic trioxide resistant acute promyelocytic leukemia cell line NB4
2013-08-02 | E-GEOD-42031 | biostudies-arrayexpress
Project description:Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia, that is generally driven by PML-RARA, resulting from a balanced chromosomal translocation t(15;17) (q24.1;q21.2). However, approximately 2% of APL patients carry other variants of RARA-fusions, which pose challenges for diagnosis and treatment. Here, we report a novel t(14;17) translocation in an APL patient that gave rise to a new fusion gene, STRN3-RARA. STRN3 forms a complex called the striatin-interacting phosphatase and kinase (STRIPAK), which couples kinases to protein phosphatase 2A and regulates their activities. Like other APL patients with RARA-variants, this patient quickly relapsed after the initial response to all-trans retinoic acid (ATRA) treatment. Mechanistically, we demonstrated that STRN3-RARA, in cooperating with UTX deficiency, which was mutated in the patient, drove APL formation in mice. Additionally, we found that STRN3-RARA cells were specifically susceptible to the TNFα pathway. Inhibition of this pathway by cepharanthine, an FDA-approved drug, effectively suppressed the growth of U937 cells with STRN3-RARA expression, as well as relapsed APL cells from the patient. Taken together, our study identified a new APL fusion gene, STRN3-RARA, and validated it as a functional APL driver, providing insight into the diagnosis and treatment of non-classic APL patients.
2024-04-23 | GSE224815 | GEO
Project description:Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia, that is generally driven by PML-RARA, resulting from a balanced chromosomal translocation t(15;17) (q24.1;q21.2). However, approximately 2% of APL patients carry other variants of RARA-fusions, which pose challenges for diagnosis and treatment. Here, we report a novel t(14;17) translocation in an APL patient that gave rise to a new fusion gene, STRN3-RARA. STRN3 forms a complex called the striatin-interacting phosphatase and kinase (STRIPAK), which couples kinases to protein phosphatase 2A and regulates their activities. Like other APL patients with RARA-variants, this patient quickly relapsed after the initial response to all-trans retinoic acid (ATRA) treatment. Mechanistically, we demonstrated that STRN3-RARA, in cooperating with UTX deficiency, which was mutated in the patient, drove APL formation in mice. Additionally, we found that STRN3-RARA cells were specifically susceptible to the TNFα pathway. Inhibition of this pathway by cepharanthine, an FDA-approved drug, effectively suppressed the growth of U937 cells with STRN3-RARA expression, as well as relapsed APL cells from the patient. Taken together, our study identified a new APL fusion gene, STRN3-RARA, and validated it as a functional APL driver, providing insight into the diagnosis and treatment of non-classic APL patients.
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Project description:The aim of this study was to gain insight into the potential mechanism of resistance to arsenic trioxide (ATO). The gene expression profile of naive (NB4) (Acute promyelocytic leukemia (APL) cell line and one of its in house generated ATO resistant sub clone (NB4-VM-AsR1) was done using whole genome microarray and compared to generate the differential expression profile which will give insight into the mechanisms of ATO resistance in APL.
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Project description:Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia, that is generally driven by PML-RARA, resulting from a balanced chromosomal translocation t(15;17) (q24.1;q21.2). However, approximately 2% of APL patients carry other variants of RARA-fusions, which pose challenges for diagnosis and treatment. Here, we report a novel t(14;17) translocation in an APL patient that gave rise to a new fusion gene, STRN3-RARA. STRN3 forms a complex called the striatin-interacting phosphatase and kinase (STRIPAK), which couples kinases to protein phosphatase 2A and regulates their activities. Like other APL patients with RARA-variants, this patient quickly relapsed after the initial response to all-trans retinoic acid (ATRA) treatment. Mechanistically, we demonstrated that STRN3-RARA, in cooperating with UTX deficiency, which was mutated in the patient, drove APL formation in mice. Additionally, we found that STRN3-RARA cells were specifically susceptible to the TNFα pathway. Inhibition of this pathway by cepharanthine, an FDA-approved drug, effectively suppressed the growth of U937 cells with STRN3-RARA expression, as well as relapsed APL cells from the patient. Taken together, our study identified a new APL fusion gene, STRN3-RARA, and validated it as a functional APL driver, providing insight into the diagnosis and treatment of non-classic APL patients.
2024-04-23 | GSE239350 | GEO
Project description:Here we report a new fusion gene, STRN3-RARA, in acute promyelocytic leukemia (APL). It cooperates with UTX deficiency to drive full-blown APL in mice. Although STRN3-RARA leukemia quickly relapses after all-trans retinoic acid treatment, it can be restrained by cepharanthine.
2024-04-23 | GSE224816 | GEO
Project description:To identify the top 20 up-regulated genes in NB4 TRIB3 shRNA cells in comparison with NB4 control shRNA cells, we examined the microarray gene expression profile of these groups above. Despite the fact that combined therapy of all-trans retinoic acid (ATRA) with arsenic trioxide (ATO) or chemotherapy dramatically improves the prognosis of patients with acute promyelocytic leukemia (APL), these regimens can cause systemic infections and secondary leukemias. Here we report that expression of the pseudokinase Tribble 3 (TRIB3) associates positively with APL progression and therapeutic resistance. The elevated TRIB3 expression promotes APL by interacting with PML-RARa and suppressing its sumoylation, ubiquitylation and degradation. This represses PML nuclear body assembly, p53-mediated senescence, cell differentiation, and supports cellular self-renewal. Genetically inhibiting Trib3 expression or disturbing the TRIB3/PML-RARa interaction produces potent therapeutic efficacy against APL and has synergic anti-APL effects when used in combination with ATRA or ATO by promoting PML-RARa degradation and PML expression. Our study provides new insight into APL pathogenesis and a new therapeutic option against APL.
2017-05-12 | GSE95637 | GEO
Project description:To identify the top 20 up-regulated genes in CD34+ cells from AML patients in comparison with healthy donors, we examined the microarray gene expression profile of CD34+ blasts from patients with newly diagnosed AML vs CD34+ normal cells from healthy donors. Despite the fact that combined therapy of all-trans retinoic acid (ATRA) with arsenic trioxide (ATO) or chemotherapy dramatically improves the prognosis of patients with APL, these regimens can cause systemic infections and secondary leukemias. Here we report that expression of the pseudokinase Tribble 3 (TRIB3) associates positively with APL progression and therapeutic resistance. The elevated TRIB3 expression promotes APL by interacting with PML-RARa and suppressing its sumoylation, ubiquitylation and degradation. This represses PML nuclear body assembly, p53-mediated senescence, cell differentiation, and supports cellular self-renewal. Genetically inhibiting Trib3 expression or disturbing the TRIB3/PML-RARa interaction produces potent therapeutic efficacy against APL and has synergic anti-APL effects when used in combination with ATRA or ATO by promoting PML-RARa degradation and PML expression. Our study provides new insight into APL pathogenesis and a new therapeutic option against APL.
2017-05-12 | GSE90062 | GEO
Project description:Acute promyelocytic leukemia (APL) is a hematological disease characterized by a balanced reciprocal translocation that leads to the synthesis of the oncogenic fusion protein PML-RARα. APL is mainly managed by a differentiation therapy based on the administration of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). However, therapy resistance, differentiation syndrome, and relapses require the development of new low-toxicity therapies based on the induction of blasts differentiation. Here, we performed a high-throughput gene expression profile of the maturation inducible APL cell line NB4 untreated or exposed to ATRA.
2020-11-05 | GSE155779 | GEO
Project description:About 5-10% newly diagnosed and about 20-30% of relapsed acute promyelocytic leukemia (APL) patients will have disease recurrence after receiving currently accepted standards of care. While there are reports of micro-environment mediated drug resistance (EM-DR) in AML, there is no data on the effect of malignant promyelocyte and stromal interaction on Arsenic trioxide (ATO) induced apoptosis. We undertook a preliminary study to evaluate the role of EM-DR to ATO in APL. In direct co-culture (contact dependent system) of malignant promyelocyte with stromal cells, the stromal cells gave a significant protective effect against ATO at different concentrations used (1 to 8 μmol; NB4 (APL cell line) In a gene expression profiling comparing NB4 cells in co-culture with NB4 cells alone, 1846 genes were differentially regulated. On a preliminary analysis, we observed an up-regulation of various pathways such as adhesion (ITGB1, ITGB2, ITGB7, etc.), Cytokines (IL-6, IL-8, IL-18, CCL2, CCL10, etc.) Wnt signalling (Wnt5a, Wnt11, NFATC4, etc,) NF-kB pathway (ICAM1, BIRC2, BIRC3, XIAP1, etc.) in the leukemic cells. The NF-kB pathway has been validated using real time PCR which correlated with the genes being differentially regulated in NB4 cells co-cultured in stroma. Agilent one-color experiment,Organism: Homo sapiens ,Custom Agilent 8x60k Human Whole Genome Microarray Gene expression (AMADID: 039494) , Labeling kit: Agilent Quick-Amp labeling Kit (p/n5190-0442)
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