Abstract
Background: Cancer stem cells are a subpopulation of malignant cells that have the capacity of both self-renewal and reconstitution of the cancer. Eradication of cancer stem cells is crucial for curing the malignant disease. Previous studies in hematopoietic malignancies showed that leukemia stem cells (LSCs) in chronic myelogenous leukemia (CML) chronic phase are originated from a hematopoietic stem cell (HSC), while LSCs in acute myeloid leukemia (AML) can either be derived from HSCs or be transformed from myeloid progenitors. But in B-cell acute lymphoblastic leukemia (B-ALL), the origin of leukemia stem cells is not clear. In this study, we tested whether BCR/ABL could transform B-lineage committed CD19+ cells to LSCs.
Methods: The B-cell lymphoblastic leukemia mouse model was generated by transplanting BCR/ABL-containing retrovirus infected bone marrow (BM) cells or CD19+ cells into recipient mice. In the secondary or tertiary transplantation experiment, the GFP+ cells (leukemic cells) were isolated from primary or secondary B-ALL mice. In addition, the frequency of leukemia stem cells was determined by limited dilution assay.
Results: We found that transducing BCR/ABL in CD19+ cells can promote their colony formation in vitro and induce B-ALL like disease in vivo. However, only BCR/ABL transduced whole BM cells can be transplanted multiple times in recipient mice, and the frequency of long-term LSCs from the latter ranges from 1/135 to 1/629.
Conclusions: These studies suggest that BCR/ABL is unable to confer the long-term stemness to committed B-lymphoid progenitors and imply that CD19 chimeric antigen receptor (CAR) modified T cell therapy may not be effective in eradicating LSCs in BCR/ABL+ B-ALL.
