Figure 1.

Msr1 deletion accelerates CML development. (A) Expression of the Msr1 gene was compared among non–BCR-ABL–expressing Lin⁻Sca-1⁺c-Kit⁺ cells, BCR-ABL-expressing WT LSCs and BCR-ABL-expressing Alox5^−/− LSCs. Msr1 expression was down-regulated by BCR-ABL and restored on Alox5 deletion in LSCs. (B) Quantitative real-time PCR analysis of non–BCR-ABL–expressing Lin⁻Sca-1⁺c-Kit⁺ cells, BCR-ABL–expressing WT LSCs and BCR-ABL–expressing Alox5^−/− LSCs. Expression of the Msr1 gene was significantly down-regulated by BCR-ABL and partially rescued after Alox5 deletion in LSCs compared with WT LSCs by RT-PCR. Mean value (± SD) for each group is shown (**P < .01). (C) FACS analysis showed that MSR1 protein was down-regulated by BCR-ABL in LSCs compared with GFP⁻Lin⁻c-Kit⁺Sca-1⁺ cells that did not express BCR-ABL. (D) FACS analysis showed that MSR1 protein was up-regulated by Alox5 deletion in LSCs compared with WT LSCs. (E) Kaplan-Meier survival curves for recipients of BCR-ABL–transduced bone marrow cells from WT or Msr1^−/− donor mice. All recipients of BCR-ABL–transduced bone marrow cells from Msr1^−/− donor mice developed CML and died within 3 weeks post bone marrow transplantation, whereas recipients of BCR-ABL–transduced bone marrow cells from WT donor mice survived longer. (F) FACS analysis showed a higher percentage of GFP⁺Gr-1⁺ cells in the bone marrow and spleens of recipients of BCR-ABL–transduced bone marrow cells from Msr1^−/− than WT donor mice (**P < .01). (G) Gross pathology and (H) H&E staining of the lungs and spleens showed severe lung hemorrhages and splenomegaly in recipients of BCR-ABL–transduced bone marrow cells from Msr1^−/− donor mice. Recipient of pMSCV-GFP–transduced bone marrow cells was shown as a control.