Transcriptomic differences in murine AML bone marrow samples with different Gab2 genotypes
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE182624 | GEO | 2022/04/27
REPOSITORIES: GEO
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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
Project description:Oligonucleotide expression microarray data used for expression signature associated with FLT3 internal tandem duplications(FLT3-ITD) in samples from older patients with cytogenetically normal AML
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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.
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Project description:Internal tandem duplications (ITD) in the receptor tyrosine kinase FLT3 occur in 25% of acute myeloid leukemia (AML) patients and lead to constitutive activation of FLT3, driving leukemia cell survival and proliferation. Quizartinib, crenolanib and gilteritinib are second-generation FLT3 inhibitors (FLT3i) in phase III trials or clinical use for the targeted treatment of FLT3-ITD+ AML. However, they demonstrated only limited benefit and were not curative. A full understanding of cellular resistance factors contributing to this poor response is lacking. Here, we examined cell-autonomous pathways modulated by FLT3i using global translatome and phosphoproteome proteomics to identify non-genetic resistance mechanisms.
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Project description:Internal tandem duplications (ITD) in the receptor tyrosine kinase FLT3 occur in 25% of acute myeloid leukemia (AML) patients and lead to constitutive activation of FLT3, driving leukemia cell survival and proliferation. Quizartinib, crenolanib and gilteritinib are second-generation FLT3 inhibitors (FLT3i) in phase III trials or clinical use for the targeted treatment of FLT3-ITD+ AML. However, they demonstrated only limited benefit and were not curative. A full understanding of cellular resistance factors contributing to this poor response is lacking. Here, we examined cell-autonomous pathways modulated by FLT3i using global translatome and phosphoproteome proteomics to identify non-genetic resistance mechanisms.
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Project description:Cytogenetically normal acute myeloid leukemia (CN-AML) represents nearly 50% of human acute myeloid leukemia (AML) cases with a 5-year overall survival of approximately 30%. In CN-AML with poorer prognosis, mutations in the de novo DNA methyltransferase (DNMT3A) and the FMS-like tyrosine kinase 3 (Flt3) commonly co-occur (1-3). We demonstrate that mice with Flt3-internal-tandem duplication (Flt3ITD) and inducible deletion of Dnmt3a spontaneously develop a rapidly-lethal, completely-penetrant, and transplantable AML of normal karyotype. These murine AML retain a single Dnmt3a floxed allele, revealing the oncogenic potential of Dnmt3a haploinsufficiency. FLT3-ITD/DNMT3A-mutant primary human and murine AML demonstrate a similar pattern of global DNA methylation. In the murine model, rescuing DNMT3A expression was accompanied by DNA re-methylation and loss of clonogenic potential, suggesting that Dnmt3a-mutant oncogenic effects are reversible. Differentially methylated genomic regions were associated with changes in the expression of nearby genes. Moreover, dissection of the cellular architecture of the AML model using single-cell RNA-Seq, flow cytometry and colony assays identified clonogenic subpopulations that differentially express genes that are sensitive to the methylation of nearby genomic loci and varied in response to Dnmt3a levels. Thus, Dnmt3a haploinsufficiency transforms Flt3ITD myeloproliferative disease by modulating methylation-sensitive gene expression within a clonogenic AML subpopulation. To identify the gene expression changes associated with Dnmt3a loss of function in human and murine Flt3-ITD and Dnmt3a-mutant AML (Single Cell RNA-Seq).
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Project description:Cytogenetically normal acute myeloid leukemia (CN-AML) represents nearly 50% of human acute myeloid leukemia (AML) cases with a 5-year overall survival of approximately 30%. In CN-AML with poorer prognosis, mutations in the de novo DNA methyltransferase (DNMT3A) and the FMS-like tyrosine kinase 3 (Flt3) commonly co-occur (1-3). We demonstrate that mice with Flt3-internal-tandem duplication (Flt3ITD) and inducible deletion of Dnmt3a spontaneously develop a rapidly-lethal, completely-penetrant, and transplantable AML of normal karyotype. These murine AML retain a single Dnmt3a floxed allele, revealing the oncogenic potential of Dnmt3a haploinsufficiency. FLT3-ITD/DNMT3A-mutant primary human and murine AML demonstrate a similar pattern of global DNA methylation. In the murine model, rescuing DNMT3A expression was accompanied by DNA re-methylation and loss of clonogenic potential, suggesting that Dnmt3a-mutant oncogenic effects are reversible. Differentially methylated genomic regions were associated with changes in the expression of nearby genes. Moreover, dissection of the cellular architecture of the AML model using single-cell RNA-Seq, flow cytometry and colony assays identified clonogenic subpopulations that differentially express genes that are sensitive to the methylation of nearby genomic loci and varied in response to Dnmt3a levels. Thus, Dnmt3a haploinsufficiency transforms Flt3ITD myeloproliferative disease by modulating methylation-sensitive gene expression within a clonogenic AML subpopulation. To identify the gene expression changes associated with Dnmt3a loss of function in human and murine Flt3-ITD and Dnmt3a-mutant AML (Bulk RNA-Seq).
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Project description:FLT3-ITD mutations are found in 30% of acute myeloid leukemia (AML) and portend a poor prognosis. Patient AML samples with FLT3-ITD express high levels of RUNX1, a transcription factor with known tumor-suppressor function. Using an inducible system, we demonstrate that RUNX1 cooperates with FLT3-ITD to trigger AML and that RUNX1 expression as well as its Tyr-phosphorylation is necessary for both initiation and maintenance of leukemogenesis. Inactivating RUNX1 in tumors released the differentiation block and downregulated genes controlling ribosome biogenesis. We identified Hhex as a direct target of RUNX1 and FLT3-ITD stimulation and confirmed high HHEX expression levels in FLT3-ITD AMLs. Importantly, HHEX could replace RUNX1 in AML induction with FLT3-ITD. These results establish and elucidate the unanticipated oncogenic function of RUNX1 in AML.
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Project description:FLT3-ITD mutations are found in 30% of acute myeloid leukemia (AML) and portend a poor prognosis. Patient AML samples with FLT3-ITD express high levels of RUNX1, a transcription factor with known tumor-suppressor function. Using an inducible system, we demonstrate that RUNX1 cooperates with FLT3-ITD to trigger AML and that RUNX1 expression as well as its Tyr-phosphorylation is necessary for both initiation and maintenance of leukemogenesis. Inactivating RUNX1 in tumors released the differentiation block and downregulated genes controlling ribosome biogenesis. We identified Hhex as a direct target of RUNX1 and FLT3-ITD stimulation and confirmed high HHEX expression levels in FLT3-ITD AMLs. Importantly, HHEX could replace RUNX1 in AML induction with FLT3-ITD. These results establish and elucidate the unanticipated oncogenic function of RUNX1 in AML.
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Project description:FLT3 activating mutations cause myeloproliferative neoplasms by deregulating hematopoietic progenitor cell growth, and acute myeloid leukemia is on the rise. Investigational drugs targeting mutant FLT3, including Quizartinib and Crenolanib, develop inherent and acquired resistance to FLT3 targeted therapy. FLT3 inhibitor resistance in AML is dependent on co-occurring mutations, parallel survival pathways, and/or subsequent FLT3-ITD mutations. Despite the high prevalence of FLT3 mutations and their clinical significance in AML, there are few targeted therapeutic options. We identified two novel naphthyridine-based FLT3 inhibitors (HSN608 and HSN748) that specifically target FLT3-ITD at sub-nanomolar concentrations and are effective against drug-resistant secondary mutations. In the current study, we evaluated these compounds antileukemic activity against FLT3-ITD and gatekeeper mutations in drug-resistant AML, relapsed/refractory AMLs with FLT3 mutations, and in vivo mouse models with combinations of epigenetic mutations TET2 with FLT3-ITD, and AML patients PDX. In these model systems, we demonstrate that HSN748 outperforms the FDA-approved FLT3 inhibitor Gilteritinib in terms of inhibitory activity against FLT3-ITD.
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