The functional interplay between the t(9;22)-associated fusion proteins BCR/ABL and ABL/BCR in Philadelphia chromosome-positive acute lymphatic leukemia.

Abstract

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/AB)L 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.

• Authors: Anahita Rafiei, Afsar Ali Mian, Claudia Döring, Anna Metodieva, Claudia Oancea, Frederic B Thalheimer, Martin Leo Hansmann, Oliver Gerhard Ottmann, Martin Ruthardt
• Journal: PLoS genetics (PLoS Genet) Vol. 11 Issue 4 Pg. e1005144 (Apr 2015) ISSN: 1553-7404 [Electronic] United States
• PMID: 25919613 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Fusion Proteins, bcr-abl

Topics

• Cell Line, Tumor
• Chromosomes, Human, Pair 22 (genetics)
• Chromosomes, Human, Pair 9 (genetics)
• Fusion Proteins, bcr-abl (biosynthesis, genetics)
• Gene Expression Regulation, Leukemic
• Hematopoietic Stem Cells (pathology)
• Humans
• Philadelphia Chromosome
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (genetics, pathology)
• Translocation, Genetic (genetics)