The Study Of The Pathogenesis Of B-cell Acute Lymphoblastic Leukemia Induced By BCR-ABL

BCR-ABL,which is generated by the Philadelphia chromosome(Ph),is one of the best-known fusion genes in hematopoietic malignancy.The chimeric protein is found in almost all of human chronic myelogenous leukemia(CML)and also accounts for approximately 20% of adult B-cell acute lymphoblastic leukemia(B-ALL)as well as 5% of pediatric B-ALL.Despite ABL/Src tyrosine kinase inhibitor therapy having dramatically improved the outcome of CML,there are still several issues unsolved such as drug resistance,relapse after therapy cessation,etc.Moreover,owing to the poor efficacy of sole ABL kinase inhibitor in treating Ph+ B-ALL,it is still worthy of further investigation of the pathogenesis of B-ALL induced by BCR-ABL.It has been shown that the ABL carboxyl terminal region(CTR)is required for the onset of B-ALL induced by v-Abl in mice.In this study,we investigated the role of the CTR in BCR-ABL induced leukemogenesis using the mouse bone marrow transduction/transplantation(BMT)model.We found that CTR is required for BCR-ABL-induced B-ALL but not for CML.The ablation of CTR in BCR-ABL(BCR-ABL?C)in myeloid cells gave rise to a MPD-like disease efficiently,similar to that induced by full-length BCR-ABL.Leukemia stem cells are from a subpopulation of the bulk tumor that have a capacity of self-renewal and can initiate a full-blown disease.Some similarities between leukemia stem cells and normal hematopoietic stem cells imply that there might be certain biological relevancy in cell origin.In our study,we tested whether BCR/ABL could transform B-lineage committed CD19+ cells to LSCs.We found that transducing BCR/ABL in CD19+ cells can render cytokine-independent growth in vitro and induce B-ALL like disease in vivo.However,only BCR/ABL transduced bone marrow cells,but not CD19+ cells,can be serially transfered multiple times into recipient mice,and the frequency of long-term LSCs ranges from 1/100 to 1/1000.These studies suggest that LSCs in BCR/ABL+ B-ALL may originate from CD19- hematopoietic stem/progenitor cells.