HDAC8i/NAMPTi combination on the transcriptomes of leukemia initiating cells of AML patients
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE161397 | GEO | 2021/02/10
REPOSITORIES: GEO
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Project description:CRISPR knockout screening on MOLM-13 cells with KPT-9274
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Project description:Ovarian cancer follows a characteristic progression pattern, forming multiple tumor masses enriched with cancer stem cells (CSCs) within the abdomen. Most patients become resistant to standard platinum-based drugs, necessitating a change in treatment approach. To target CSCs, inhibiting NAMPT, which is the rate-limiting enzyme in the salvage pathway for NAD+ synthesis, has been explored. KPT-9274 is an innovative drug targeting both NAMPT and PAK4. However, its effectiveness against ovarian cancer had not been validated. Here, we show the efficacy and mechanisms of KPT-9274 in treating 3D-cultured spheroids that are resistant to platinum-based drugs. In these spheroids, KPT-9274 not only inhibited NAD+ production in NAMPT-dependent cell lines, but also suppressed NADPH and ATP production, indicating reduced mitochondrial function. It also downregulated expression of inflammation and gene repair-related genes. Moreover, by altering PAK4's mostly cytoplasmic localization, the compound hindered kinase activity, leading to decreased phosphorylation of S6 Ribosomal protein, AKT, and β-Catenin in the cytoplasm and its suppression was NAD+- dependent. These findings suggest that KPT-9274 could be a promising treatment for ovarian cancer patients resistant to platinum drugs, emphasizing the need for precision medicine to identify the specific NAD+-producing pathway a tumor relies on before treatment.
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Project description:Differences in chemo-sensitivity of subpopulations of AML stem cells could have important clinical implications. Using in vitro cytotoxicity, xenograft models and colony forming assays, we compared chemotherapy sensitivity between Lineage (Lin-)CD34-CD38-, Lin-CD34-CD38+, Lin-CD34+CD38- and Lin-CD34+CD38+ populations from 26 primary AMLs (19 paediatric and 7 adult). We identified a common recurring pattern of chemo-response associated with a poor clinical outcome: In each of 16/26 (62%) AMLs, Lin-CD34-CD38- cells were the most chemoresistant of the four subpopulations to daunorubicin in vitro. Cytarabine-resistant colonies formed only from Lin-CD34-CD38- populations following tertiary passages through both NOG mice and methylcellulose in these AMLs The presence of chemo-resistant Lin-CD34-CD38- populations was signficantly associated with reduced relapse-free survival in childhood AML. Consistently, CD34 negativity was significantly associated with an increased risk of relapse in a larger retropsective cohort (n=89). Samples enriched for chemo-resistant Lin-CD34-CD38- LSCs with a stem cell profile and an undifferentiated genotype revealed pathways likely to confer chemo-resistance, These strongly indicated dependence of chemo-resistant Lin-CD34-CD38- LSCs on their niche environment as well as deregulated DNA damage responses, lipid and Notch1 signalling, Our findings have major implications for the risk stratification of childhood AML and could lead to the development of novel therapeutic approaches.
2015-03-01 | GSE45249 | GEO
Project description:Differences in chemo-sensitivity of subpopulations of AML stem cells could have important clinical implications. Using in vitro cytotoxicity, xenograft models and colony forming assays, we compared chemotherapy sensitivity between Lineage (Lin-)CD34-CD38-, Lin-CD34-CD38+, Lin-CD34+CD38- and Lin-CD34+CD38+ populations from 26 primary AMLs (19 paediatric and 7 adult). We identified a common recurring pattern of chemo-response associated with a poor clinical outcome: In each of 16/26 (62%) AMLs, Lin-CD34-CD38- cells were the most chemoresistant of the four subpopulations to daunorubicin in vitro. Cytarabine-resistant colonies formed only from Lin-CD34-CD38- populations following tertiary passages through both NOG mice and methylcellulose in these AMLs The presence of chemo-resistant Lin-CD34-CD38- populations was signficantly associated with reduced relapse-free survival in childhood AML. Consistently, CD34 negativity was significantly associated with an increased risk of relapse in a larger retropsective cohort (n=89). Samples enriched for chemo-resistant Lin-CD34-CD38- LSCs with a stem cell profile and an undifferentiated genotype revealed pathways likely to confer chemo-resistance, These strongly indicated dependence of chemo-resistant Lin-CD34-CD38- LSCs on their niche environment as well as deregulated DNA damage responses, lipid and Notch1 signalling, Our findings have major implications for the risk stratification of childhood AML and could lead to the development of novel therapeutic approaches. 3 subpopulations of leukemia stem cells from 9 patients with primary childhood AML were analysed. We compared gene expression profiles of Lin-CD34+CD38- (Q1), Lin-CD34+CD38+ (Q2) and Lin-CD34-CD38- (Q3) cells between 3 AMLs in which the CD34+ cells were most chemo-resistant (AML-1P, AML-6P and AML-10P) and the same cells from the remaining AMLs in which the Lin-CD34-CD38- cells were the most chemo-resistant population. We also compared the gene expression profiles of Lin-CD34-CD38- (Q3) cells in the 3 samples with the highest LC50 values (AML-15P, AML-17P and AML-19P) with that of the 3 AMLs exhibiting the lowest LC50 values (AML-2P, AML-5P and AML-11P).
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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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