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CircMYBL2 Regulates FLT3-ITD FLT3AML Translation in AML

ABSTRACT: CircMYBL2 is more highly expressed in AML patients with FLT3-ITD mutations than in those without the FLT3-ITD mutation. We found that circMYBL2 knockdown specifically inhibits proliferation and promotes the differentiation of FLT3-ITD AML cells in vitro and in vivo. We used the ribosome profiling and RNA-seq libraries sequenced with Illumina HiSeq 2500 to identify the mRNA that circMYBL2 targeted. Interestingly, we found that circMYBL2 significantly influences the protein level of mutant FLT3 kinase, which contributes to the activation of FLT3-ITD-dependent signaling pathways. Mechanistically, circMYBL2 enhanced the translational efficiency of FLT3 kinase by increasing the binding of PTBP1 to FLT3 mRNA. Moreover, circMYBL2 knockdown impaired the cytoactivity of inhibitor-resistant FLT3-ITD-positive cells, with a significant decrease in FLT3 kinase expression, followed by the inactivation of its downstream pathways. In summary, we are the first to reveal a circRNA that specifically influences FLT3-ITD AML and regulates FLT3 kinase levels through translational regulation, suggesting that circMYBL2 may be a potential therapeutic target for FLT3-ITD AML.

ORGANISM(S): Homo sapiens

PROVIDER: GSE133925 | GEO | 2019/07/09

REPOSITORIES: GEO

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PRMT1-mediated FLT3 arginine methylation is required for maintenance of FLT3-ITD+ Acute Myeloid Leukemia

Project description:The presence of FLT3-ITD mutations in patients with acute myeloid leukemia (AML) is associated with poor clinical outcome. FLT3 tyrosine kinase inhibitors (TKIs), although effective in kinase ablation, do not eliminate FLT3-ITD+ leukemia stem cells (LSCs) which are potential sources of disease relapse, prompting us to ask whether FLT3-ITD protein regulates the AML LSCs survival through a kinase-independent mechanism. Here, we show that expression of PRMT1, the primary type I arginine methyltransferase, significantly increases in LSC-enriched CD34+CD38- populations relative to normal counterparts. Genetic PRMT1 depletion blocked AML CD34+ cell survival, and had more potent effects in AML cells from patients harboring FLT3-ITD. Our genome wide analysis of gene expression and PRMT1 conditional KO mouse study confirmed that PRMT1 preferentially cooperates with FLT3-ITD contributing to AML cell maintenance. Mechanistically, PRMT1 catalyzed FLT3-ITD protein methylation at arginines 972/973, and PRMT1 promoted leukemia cell growth in a FLT3 methylation-dependent manner. Moreover, effects of FLT3-ITD methylation in AML cells were in part due to crosstalk with FLT3-ITD phosphorylation at tyrosine 969 (Y969). Importantly, FLT3 methylation persisted in FLT3-ITD+ AML cells following TKI (AC220) treatment, indicating that methylation occurs independently of kinase activity. Finally, in both patient-derived xenograft (PDX) and murine AML models, combined administration of AC220 with a type I PRMT inhibitor (MS023) enhanced elimination of FLT3-ITD+ AML relative to AC220 treatment alone. Our study demonstrates that PRMT1-mediated FLT3 methylation promotes LSC activity and suggests that combining PRMT1 inhibition with FLT3 TKI treatment could be a promising approach to selectively target FLT3-ITD+ LSCs.

2021-11-10 | GSE122435 | GEO

FLT3 inhibition upregulates HDAC8 via FOXO to inactivate p53 and promote maintenance of FLT3-ITD+ acute myeloid leukemia

Project description:Internal tandem duplication (ITD) mutations within the FMS-like receptor tyrosine kinase-3 (FLT3) can be found in up to 25~30% of acute myeloid leukemia (AML) patients and confer a poor prognosis. Although FLT3 tyrosine kinase inhibitors (TKIs) have shown clinical responses, the overall outcome of FLT3-ITD+ AML patients remains poor, and most of them would relapse very shortly. TKIs can not eliminate primitive FLT3-ITD+ AML cells, which are potential sources of relapse. Therefore, elucidating the mechanisms underlying FLT3-ITD+ AML maintenance and drug resistance is essential to develop novel, effective treatment strategies. Here, we demonstrate that FLT3 inhibition induces histone deacetylase 8 (HDAC8) upregulation through FOXO1 and FOXO3-mediated transactivation in FLT3-ITD+ AML cells. Upregulated HDAC8 deacetylates and inactivates p53, leading to leukemia maintenance and drug resistance upon TKIs treatment. Genetic or pharmacological inhibition of HDAC8 re-activates p53, abrogates leukemia maintenance and significantly enhances TKI-mediated elimination of FLT3-ITD+ AML cells. Importantly, in FLT3-ITD+ AML patient-derived xenograft models, the combination of FLT3 TKI (AC220) with a HDAC8 inhibitor (22d) significantly inhibits leukemia progression and effectively reduces primitive FLT3-ITD+ AML cells. Moreover, we extend these findings to an AML subtype harboring another tyrosine kinase activating mutation. In conclusion, our study demonstrates that HDAC8 upregulation as an important mechanism to resist TKIs and promote leukemia maintenance, and suggests that combining HDAC8 inhibition with TKI treatment could be a promising strategy to treat FLT3-ITD+ AML and other tyrosine kinase mutation-harboring leukemias.

2020-02-13 | GSE138057 | GEO

GRP94 rewires and buffers the FLT3-ITD signaling network and promotes survival of acute myeloid leukemic stem cells

Project description:Internal tandem duplications in the tyrosine kinase receptor FLT3 (FLT3-ITD) are among the most common lesions in acute myeloid leukemia (AML) and there exists a need for new forms of treatment. Using ex vivo drug sensitivity screening, we found that FLT3-ITD+ patient cells are particularly sensitive to HSP90 inhibitors. While it is well known that HSP90 is important for FLT3-ITD stability, we found that HSP90 family members play a much more complex role in FLT3-ITD signaling than previously appreciated. First, we found that FLT3-ITD activates the unfolded protein response (UPR), leading to increased expression of GRP94/HSP90B1. GRP94 rewires FLT3-ITD signaling by binding and retaining FLT3-ITD in the ER, where it aberrantly activates downstream signaling pathways. Second, HSP90 family proteins protect FLT3-ITD+ AML cells against apoptosis by alleviating proteotoxic stress, and treatment with HSP90 inhibitors results in proteotoxic overload that triggers UPR-induced apoptosis. Importantly, leukemic stem cells are strongly dependent upon HSP90 for their survival, and the HSP90 inhibitor ganetespib causes leukemic stem cell exhaustion in mouse PDX models. Taken together, our study reveals a molecular basis for HSP90 addiction of FLT3-ITD+ AML cells and provides a rationale for including HSP90 inhibitors in the treatment regime for FLT3-ITD+ AML.

2020-09-02 | PXD009423 | Pride

Deacetylation of YAP1 promotes the resistance to chemo-and targeted therapy in FLT3-ITD + AML cells

Project description:The FLT3-ITD mutation occurs in about 30% of acute myeloid leukemia (AML) and is associated with poor prognosis. However, FLT3 inhibitors are only partially effective and prone to acquired resistance. Here, we identified Yes-associated protein 1 (YAP1) as a tumor suppressor in FLT3-ITD+ AML. YAP1 inactivation conferred FLT3-ITD+ AML cells resistance to chemo- and targeted therapy. Mass spectrometric assay revealed DNA damage repair gene poly (ADP-ribose) polymerase 1 (PARP1) might be the downstream of YAP1, and the pro-proliferative effect by YAP1 knockdown were partly reversed via PARP1 inhibitor. Importantly, histone deacetylase 10 (HDAC10) contributed to decreased YAP1 acetylation levels through histone H3 lysine 27 (H3K27) acetylation, leading to the reduced nuclear accumulation of YAP1. Selective HDAC10 inhibitor chidamide or HDAC10 knockdown activated YAP1, enhanced DNA damage and significantly attenuated FLT3-ITD+ AML cells resistance. Additionally, combination chidamide with FLT3 inhibitors or chemotherapy agents synergistically inhibited growth and increased apoptosis of FLT3-ITD+AML cell lines and acquired resistant cells from the relapse FLT3-ITD+ AML patients. These findings demonstrate that the HDAC10-YAP1-PARP1 axis maintains FLT3-ITD+ AML cells and targeting this axis might improve clinical outcomes in FLT3-ITD+ AML patients._x001F__x001F__x001F__x001F_

2022-02-09 | GSE196258 | GEO

Microenvironmental CXCL12 Deletion Enhances Flt3-ITD Acute Myeloid Leukemia Stem Cell Response to Therapy by Reducing p38 MAPK Signaling

Project description:Fms-like tyrosine kinase 3 (Flt3) tyrosine kinase inhibitors (Flt3-TKI) have improved outcomes for patients with Flt3-mutated acute myeloid leukemia (AML) but are limited by resistance and relapse, suggesting persistence of leukemia stem cells (LSC). Here we utilized a Flt3-internal tandem duplication (Flt3-ITD) and Tet2-deleted AML genetic mouse model to characterize Flt3-ITD AML LSC and their resistance to Flt3-TKI. We show that LSC were enriched within the primitive ST-HSC population. CXCl12-expressing osteoprogenitors were increased in the Flt3-ITD AML marrow and FLT3-ITD LSC showed increased expression of the CXCL12 receptor CXCR4. CXCL12 deletion from the microenvironment enhanced AML targeting by combined Flt3-TKI and chemotherapy treatment with enhanced LSC targeting. We found that both treatment and CXCL12 deletion partially reduced p38 mitogen-activated protein kinase (p38) signaling with increased, but not complete, reduction seen with combined treatment and CXCL12 deletion. Our studies suggest that p38 contributes to CXCL12-mediated maintenance of AML LSC following Flt3-TKI and chemotherapy treatment, but that p38 inhibition enhances AML LSC response to treatment to a greater extent than CXCL12 deletion alone. This study supports a role for p38 signaling in CXCL12-mediated protection of AML LSC from treatment and provide a rationale for targeting p38 signaling to enhance Flt3-ITD AML targeting.

2024-01-03 | GSE212428 | GEO

Gene expression analysis of Ba/F3-ITD cells treated with DMSO or sorafenib

Project description:The aim of the study is to analyse whether the Sorafenib renders FLT3-ITD-positive acute myeloid leukemia (AML) cells more immunogenic . We used Ba/F3-ITD cells as a model cell line to study the effect of Sorafenib on FLT3-ITD-positive AML cells. Ba/F3-ITD cells are murine pro-B cell lines with a stable FLT3-ITD expression. Ba/F3-ITD cells were treated with DMSO or 10nM sorafenib for 24 hours. Cells were harvested and total RNA was isolated

2018-02-01 | E-MTAB-4487 | biostudies-arrayexpress

Crenolanib in combination with azacitidine abrogates stromal protection and survival of leukemia-initiating cells in FLT3-ITD+ AML

Project description:Effectively targeting leukemia-initiating cells (LIC) in FLT3-internal-tandem-duplication (ITD)-mutated acute myeloid leukemia (AML) remains a crucial goal for achievement of cure. FLT3 tyrosine kinase inhibitors (TKI) have limited impact as single agents and have thus far been unable to eradicate LIC enriched in the CD34+CD38- bone marrow compartment and protected by contact with niche cells.Using primary AML samples in vitro as well as in an in vivo xenograft model, we investigated whether combining the novel FLT3-selective TKI crenolanib with the hypomethylating agent azacitidine (AZA) can eliminate LIC in FLT3-ITD+ AML and determined whether efficacy of this combination is dependent on coexisting genetic mutations in DNMT3A, NPM1 and TET2. Our data show that crenolanib as a single agent was unable to target FLT3-ITD+ LIC in contact with niche cells while the addition of AZA overcame stromal protection and resulted in dramatically reduced clonogenic capacity of FLT3-ITD+ LIC in vitro as well as severely impaired engraftment capacity of FLT3-ITD+ LIC in NSG mice. Strikingly, FLT3-mutated AML samples harboring concurrent TET2 mutations were completely resistant to crenolanib as a single agent. Mutations in DNMT3A or NPM1 had no influence on response to crenolanib while DNMT3A mutations conferred increased sensitivity of FLT3-ITD+ LIC to AZA. Our data suggest that response to crenolanib or AZA as single agents in FLT3-ITD+ AML is highly dependent on coexisting mutations in epigenetic regulators. However, the combination of AZA + crenolanib effectively eliminated FLT3-ITD+ LIC irrespective of additional mutations in NPM1, DNMT3A or TET2.

2017-04-03 | GSE86021 | GEO

Molecular variability of FLT3/ITD mutants and their impact on the differentiation program of 32D cells

Project description:FLT3 is the most frequently mutated gene in AML â up to 40% of AML harbor an activating mutation within FLT3 gene. Though AML is a relatively rare disease, such a high mutability rate, as observed with FLT3 gene, is striking. To elucidate the molecular background of this phenomenon, we have established nine unique FLT3/ITD - carrying 32D cell lines and a set of controls, and subjected them to whole genome expression analysis and 2DE LC/MS proteomics. Data obtained on this so far largest set of ITD mutants indicates that in comparison to the wild type FLT3 expressing 32D cells and transduction controls, FLT3/ITD positive cells exhibit less mature expression profiles resembling ST-HSC and MkEP/CMP/LMPP progenitors. We hypothesize that FLT3/ITD might contribute not only to the proliferative advantage of FLT3/ITD positive cells, but also to their reprogramming towards less differentiated stages, thus strengthening their malignant properties. This finding might explain the pronounced mutation rate of the aberrantly expressed FLT3 gene in AML, and, also, the inferior prognosis of FLT3/ITD positive AML patients. Moreover, the microarray data has revealed biological differences among individual ITD variants â a finding supporting the recent clinical data on the prognostic impact of the size of individual ITDs. Keywords: genetic modification Nine stable 32D cell lines harboring unique human FLT3/ITD mutants, two parental 32 cell lines, two 32D stable cell lines harboring cloning vector only, and two 32D cell lines stably expressing human wild type FLT3 were subjected to the microarray analysis.

2010-04-08 | E-GEOD-12766 | biostudies-arrayexpress

FLT3-ITD mutation expands dendritic cells and alters CD4+ T cells in acute myeloid leukemia

Project description:Fms-like tyrosine kinase 3 (FLT3) is a critical receptor for functional dendritic cell (DC) development. Mutations associated with FLT3 are commonly observed in acute myeloid leukemia (AML) patients. Internal tandem duplication (FLT3-ITD) results in ligand-independent constitutive signaling and promotes tumor survival. Basic characterization of dendritic cells in the context of AML is lacking, therefore we investigated how FLT3-ITD impacts DC homeostasis and what downstream affects on the immune system may be. During AML we found that patient bone marrow DC homesostasis is disrupted and in a mouse model of AML we found that T-bet- cDC2s are increased in vivo and both Treg and Th17 cells are increased. In vitro co-cultures of AML DCs and naive OT-II cells results in more Th17 phenotype by IL-17A secretion. We propose that in FLT3-ITD+ AML DC homeostasis is dysregulated and Th17 cells are increased as a result.

2023-08-23 | GSE238156 | GEO

Cap analysis gene analysis (CAGE) of AML cells harbouring FLT3-ITD mutations

Project description:This SuperSeries is composed of the SubSeries listed below. The purpose of the experiment is to investigate transcriptome signatures of FLT3-ITD and TKD double mutations in AML cells (primary samples and Ba/F3 cell) and the underlying molecular mechanism of mutation-driven acquired resistance. We identify 310 upregulated and 22 downregulated promoters in FLT3-ITD/D835 mutant AML cells compared to cells with FLT3-ITD (FDR<0.05), and 1945 upregulated and 1470 downregulated promoters in FLT3-ITD/D835 mutant Ba/F3 cells compared to cells with FLT3-ITD.

2023-05-08 | GSE149964 | GEO

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