Dataset Information

Role of STAT3 in Transformation and Drug Resistance in CML.

ABSTRACT: Chronic myeloid leukemia (CML) is initially driven by the bcr-abl fusion oncoprotein. The identification of bcr-abl led to the discovery and rapid translation into the clinic of bcr-abl kinase inhibitors. Although, bcr-abl inhibitors are efficacious, experimental evidence indicates that targeting bcr-abl is not sufficient for elimination of minimal residual disease found within the bone marrow (BM). Experimental evidence indicates that the failure to eliminate the leukemic stem cell contributes to persistent minimal residual disease. Thus curative strategies will likely need to focus on strategies where bcr-abl inhibitors are given in combination with agents that specifically target the leukemic stem cell or the leukemic stem cell niche. One potential target to be exploited is the Janus kinase (JAK)/signal transducers and activators of transcription 3 (STAT3) pathway. Recently using STAT3 conditional knock-out mice it was shown that STAT3 is critical for initiating the disease. Interestingly, in the absence of treatment, STAT3 was not shown to be required for maintenance of the disease, suggesting that STAT3 is required only in the tumor initiating stem cell population (Hoelbl et al., 2010). In the context of the BM microenvironment, STAT3 is activated in a bcr-abl independent manner by the cytokine milieu. Activation of JAK/STAT3 was shown to contribute to cell survival even in the event of complete inhibition of bcr-abl activity within the BM compartment. Taken together, these studies suggest that JAK/STAT3 is an attractive therapeutic target for developing strategies for targeting the JAK-STAT3 pathway in combination with bcr-abl kinase inhibitors and may represent a viable strategy for eliminating or reducing minimal residual disease located in the BM in CML.

SUBMITTER: Nair RR

PROVIDER: S-EPMC3355894 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Role of STAT3 in Transformation and Drug Resistance in CML.

Nair Rajesh R RR Tolentino Joel H JH Hazlehurst Lori A LA

Frontiers in oncology 20120410

Chronic myeloid leukemia (CML) is initially driven by the bcr-abl fusion oncoprotein. The identification of bcr-abl led to the discovery and rapid translation into the clinic of bcr-abl kinase inhibitors. Although, bcr-abl inhibitors are efficacious, experimental evidence indicates that targeting bcr-abl is not sufficient for elimination of minimal residual disease found within the bone marrow (BM). Experimental evidence indicates that the failure to eliminate the leukemic stem cell contributes ...[more]

PMID: 22649784

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Project description:Total RNA was extracted from Lin-Sca-1+c-Kit+ (LSK) cells sorted from the BM of Spred1HSCΔ/ΔSCLtTA/BCR-ABL (HSC KO) and Spred1HSCwt/wtSCLtTA/BCR-ABL (HSC wt) (n=5 mice per group, both group given 7 doses of 250μg poly(I:C), ip, every two days, to activate Mx1-cre), Spred1ECΔ/ΔSCLtTA/BCR-ABL (EC KO) and Spred1ECwt/wtSCLtTA/BCR-ABL (EC wt) (n=5 mice per group) mice using the miRNeasy micro Kit (Qiagen, Valencia, CA). SMART-Seq® Ultra Low Input RNA Kit for Sequencing – v4 (TaKaRa, Cat 634888) was used for generating amplified double stranded (ds) cDNA from each sample with 2ng of input total RNA according to the manufacturer's protocol. The resulting ds cDNA was sheared with Covaris LE220 with the setting of DNA fragment size of 200bp peak. The sheared DNA was used for sequencing library preparation by using KAPA HyperPrep Kits (Roche, Cat KK8500). The final libraries were quantified with qubit and bioanalyzer. The sequencing was performed with the single read mode of 51 cycles of read1 and 7 cycles of index read with V4 reagents on Illumina Hiseq2500. Real-time analysis (RTA) 2.2.38 software was used to process the image analysis and base calling. The nf-core RNAseq pipeline v1.3 was used to process the raw sequencing reads (https://nf-co.re). RNA-Seq reads were trimmed to remove sequencing adapters using Trimmomatic3 and polyA tails using FASTP4. The processed reads were mapped back to the mouse genome (mm10) using STAR software (v. 020201)5. The HTSeq software (v.0.6.0)6 was applied to generate the count matrix, with default parameters. Differential expression analysis was conducted by adjusting read counts to normalized expression values using TMM normalization method in R7. Briefly, for each comparison between HSC KO LSKs and HSC wt LSKs and between EC KO LSKs and EC wt LSKs, general linear models were applied to identify DEGs using TMM normalization expression level as depending variable, and genotype as independent variable. Genes with a p-value less than 0.05 and with a fold change (FC) greater than 1.5 or less than 0.7 were considered as significant up- and down-regulated genes, respectively. Pathway analysis was conducted using GSEAPreranked algorithm using GSEA Desktop program in Java8, 9. The former requires a list of up- and down-regulated genes, while the latter a ranked list of whole genes according to their log2 fold change and p-values.

Dataset Information

Role of STAT3 in Transformation and Drug Resistance in CML.

Publications

Role of STAT3 in Transformation and Drug Resistance in CML.

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