Abstract
The persistence leukemia stem cells (LSCs) in chronic myeloid leukemia (CML) despite tyrosine kinase inhibition (TKI) may explain relapse after TKI withdrawal. Here we performed genome-wide transcriptome analysis of highly refined CML and normal stem and progenitor cell populations to identify novel targets for the eradication of CML LSCs using exon microarrays. We identified 97 genes that were differentially expressed in CML versus normal stem and progenitor cells. These included cell surface genes significantly upregulated in CML LSCs: DPP4 (CD26), IL2RA (CD25), PTPRD, CACNA1D, IL1RAP, SLC4A4, and KCNK5. Further analyses of the LSCs revealed dysregulation of normal cellular processes, evidenced by alternative splicing of genes in key cancer signaling pathways such as p53 signaling (e.g. PERP, CDKN1A), kinase binding (e.g. DUSP12, MARCKS), and cell proliferation (MYCN, TIMELESS); downregulation of pro-differentiation and TGF-β/BMP signaling pathways; upregulation of oxidative metabolism and DNA repair pathways; and activation of inflammatory cytokines, including CCL2, and multiple oncogenes (e.g., CCND1). These data represent an important resource for understanding the molecular changes in CML LSCs, which may be exploited to develop novel therapies for eradication these cells and achieve cure.
Highlights
Despite the significant improvement in survival rates of chronic phase (CP) chronic myeloid leukemia (CML) patients made possible by tyrosine kinase inhibitor (TKI) therapy, cures outside of allogeneic blood or marrow transplantation are rare[1,2,3,4]
Using analysis of variance (ANOVA), we identified genes that were significantly differentially expressed between all CML vs. normal samples, regardless of sorted population, and those that were significantly differentially expressed between CD34+CD38ALDHhigh cell populations of CML and normal samples (FDR = 0.05, |log2(Fold Change)| > 1)
We previously reported that aldehyde dehydrogenase (ALDH) expression enriched for CD34+CD38- cells capable of engrafting NSG mice from normal marrow[18] as well as CML[20], presumably representing the primitive stem cell fractions in both
Summary
Despite the significant improvement in survival rates of chronic phase (CP) chronic myeloid leukemia (CML) patients made possible by tyrosine kinase inhibitor (TKI) therapy, cures outside of allogeneic blood or marrow transplantation are rare[1,2,3,4]. This appears to be due to the resistance of leukemia stem cells (LSCs) in CML to the pro-apoptotic effects of TKI agents[5,6,7,8]. BCR-ABL expression appears to be required for the survival of CML progenitors but not CML LSCs, where the BCR-ABL gene can be silent likely www.impactjournals.com/oncotarget
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