A tumor suppressor function of the Msr1 gene in leukemia stem cells of chronic myeloid leukemia
Department of Medicine, Division of Hematology Oncology
Animals; Arachidonate 5-Lipoxygenase; Cells, Cultured; Gene Expression Profiling; Gene Expression Regulation, Leukemic; Genes, Tumor Suppressor; Humans; K562 Cells; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mice; Mice, Inbred C57BL; Mice, Knockout; Microarray Analysis; Neoplasm Transplantation; Neoplastic Stem Cells; Scavenger Receptors, Class A; Transplantation, Heterologous
Cancer Biology | Hematology | Hemic and Lymphatic Diseases | Neoplasms | Oncology
We have shown that Alox5 is a critical regulator of leukemia stem cells (LSCs) in a BCR-ABL-induced chronic myeloid leukemia (CML) mouse model, and we hypothesize that the Alox5 pathway represents a major molecular network that regulates LSC function. Therefore, we sought to dissect this pathway by comparing the gene expression profiles of wild type and Alox5(-/-) LSCs. DNA microarray analysis revealed a small group of candidate genes that exhibited changes in the levels of transcription in the absence of Alox5 expression. In particular, we noted that the expression of the Msr1 gene was upregulated in Alox5(-/-) LSCs, suggesting that Msr1 suppresses the proliferation of LSCs. Using CML mouse model, we show that Msr1 is downregulated by BCR-ABL and this down-regulation is partially restored by Alox5 deletion, and that Msr1 deletion causes acceleration of CML development. Moreover, Msr1 deletion markedly increases LSC function through its effects on cell cycle progression and apoptosis. We also show that Msr1 affects CML development by regulating the PI3K-AKT pathway and beta-Catenin. Together, these results demonstrate that Msr1 suppresses LSCs and CML development. The enhancement of the tumor suppressor function of Msr1 may be of significance in the development of novel therapeutic strategies for CML.
DOI of Published Version
Blood. 2011 Jul 14;118(2):390-400. doi: 10.1182/blood-2010-11-316760. Epub 2011 May 19. Link to article on publisher's site
Chen, Yaoyu; Sullivan, Con; Peng, Cong; Shan, Yi; Hu, Yiguo; Li, Dongguang; and Li, Shaoguang, "A tumor suppressor function of the Msr1 gene in leukemia stem cells of chronic myeloid leukemia" (2011). Hematology Oncology Publications. 2.