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Ybx1 is required for Survival of Leukemia Stem Cells and the Development of Chronic Myeloid Leukemia

ABSTRACT: Chronic myeloid leukemia (CML) is a myeloproliferative disorder derived from hematopoietic stem cells (HSCs) that harbor Philadelphia chromosome (Ph chromosome). Leukemia stem cells (LSCs) in CML are insensitive to TKIs treatment, and are responsible for disease relapse. However, the molecular mechanisms for LSCs survival remains elusive. Here we show that YBX1 plays an important role in regulating survival of CML LSCs. We find that YBX1 expression is significantly increased in CML cells. Using CML patient-derived cell lines and a BCR-ABL-induced CML mouse model, we confirm that YBX1 is required for survival maintenance of LSCs. Deletion of YBX1 impairs the propagation of CML through impairing cell cycle and inducing apoptosis of LSCs. Mechanistically, we find that YBX1 regulates expression of apoptosis-related genes, and YBX1 binds MYC and BCL2 transcripts. YBX1 loss decreases expression of MYC and BCL2 by accelerating their mRNA decay. In addition, restoration of MYC and BCL2 efficiently rescue the defects of YBX1-deficient CML cells. Overall, our findings reveal a critical role of YBX1 in maintaining survival of CML LSCs, which may provide a rationale for targeting YBX1 in CML treatment.

ORGANISM(S): Mus musculus

PROVIDER: GSE199304 | GEO | 2022/03/27

REPOSITORIES: GEO

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Project description:We previously demonstrated that Alox5 deficiency impairs the function of LSCs and prevents the initiation of BCR-ABL-induced CML. To identify the pathways in which Alox5 gene regulates function of LSCs, we performed a comparative DNA microarray analysis using total RNA isolated from non-BCR-ABL-expressing Lin-Sca-1+c-Kit+, BCR-ABL-expressing wild type LSCs and BCR-ABL-expressing Alox5-/- LSCs. The result was validated by quantitative real-time PCR analysis of non-BCR-ABL-expressing Lin-Sca-1+c-Kit+, BCR-ABL-expressing wild type LSCs and BCR-ABL-expressing Alox5-/- LSCs. 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 further dissect this pathway by comparing the gene expression profiles of wild type and Alox5-/- LSCs derived from our mouse model for BCR-ABL-induced CML. 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 up-regulated in Alox5-/- LSCs, suggesting that Msr1 might suppress the proliferation of LSCs. Using our CML mouse model, we show that Msr1 is down-regulated 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 ?-Catenin. Together, these results demonstrate that Msr1 suppresses LSCs and CML development. The enhancement of Msr1 function may be of significance in the development of novel therapeutic strategies targeting CML. To identify genes that are regulated by BCR-ABL in LSCs and LSCs without Alox5 gene, we compared the gene profile between wild type(WT) LSCs or Alox5-/- LSCs.

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Ybx1 is required for Survival of Leukemia Stem Cells and the Development of Chronic Myeloid Leukemia

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