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

摘要

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 p96~( ABL/BCR )for the pathogenesis of Ph~(+)ALL. The co-expression of p96~( ABL/BCR )enhanced the kinase activity and as a consequence, the transformation potential of p185~( BCR/ABL ). Targeting p96~( ABL/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 p96~( ABL/BCR )and p185~( BCR/ABL )in hematopoietic stem cells. Co-expression of p96~( ABL/BCR )abolished the capacity of p185~( BCR/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 p96~( ABL/BCR )for the pathogenesis of Ph~(+)ALL. Author Summary The t(9;22) is a reciprocal translocation, which causes chronic myeloid leukemia (CML) and a subset of high risk acute lymphatic leukemia (ALL). The derivative chromosome 22 is the so called Philadelphia chromosome (Ph) which encodes the BCR/ABL kinase. Targeting BCR/ABL by selective ATP competitors, such as imatinib or nilotinib, is a well validated therapeutic concept, but unable to definitively eradicate the disease. Little is known about the role of the fusion protein encoded by the reciprocal derivative chromosome 9, the ABL/BCR. In models of Ph~(+)ALL we show that the functional interplay between ABL/BCR and BCR/ABL not only increases the transformation potential of BCR/ABL but is also indispensable for the growth and survival of Ph~(+)ALL leukemic cells. The presence of ABL/BCR changed the phenotype of the leukemia most likely due to its capacity to influence the stem cell population as shown by our in vivo data. Taken together our here presented data reveal an important role of p96~( ABL/BCR )for the pathogenesis of Ph~(+)ALL.