The Functional Interplay Between the t(9;22)-Associated Fusion Proteins BCR/ABL and ABL/BCR in Philadelphia Chromosome-Positive Acute Lymphatic Leukemia

The hallmark of philadelphia chromosome positive (ph+) leukemia is the bcr/abl kinase,which is successfully targeted by selective atp competitors. however,inhibition of bcr/abl alone is unable to eradicate ph+ leukemia. the t(9;22) is a reciprocal translocation which encodes not only for the der22 (philadelphia chromosome) related bcr/abl,but also for der9 related abl/bcr fusion proteins,which can be detected in 65% of patients with chronic myeloid leukemia (cml) and 100% of patients with ph+ acute lymphatic leukemia (all). abl/bcrs are oncogenes able to influence the lineage commitment of hematopoietic progenitors. aim of this study was to further disclose the role of p96abl/bcr for the pathogenesis of ph+ all. the co-expression of p96abl/bcr enhanced the kinase activity and as a consequence,the transformation potential of p185bcr/abl. targeting p96abl/bcr by rnai inhibited growth of ph+ all cell lines and ph+ all patient-derived long-term cultures (pd-ltcs). our in vitro and in vivo stem cell studies further revealed a functional hierarchy of p96abl/bcr and p185bcr/abl in hematopoietic stem cells. co-expression of p96abl/bcr abolished the capacity of p185bcr/abl to induce a cml-like disease and led to the induction of all. taken together our here presented data reveal an important role of p96abl/bcr for the pathogenesis of ph+ all. © 2015 rafiei et al.