The functional interplay between the t(9;22)-associated fusion proteins BCR/ABL and ABL/BCR in Philadelphia chromosome-positive Acute Lymphatic Leukemia

Rafiei, Anahita, Mian, Afsar Ali, Doering, Claudia, Metodieva, Anna, Oancea, Claudia ORCID: https://orcid.org/0000-0003-3758-1892, Thalheimer, Frederic B., Hansmann, Martin Leo, Ottmann, Oliver ORCID: https://orcid.org/0000-0001-9559-1330 and Ruthardt, Martin ORCID: https://orcid.org/0000-0003-1021-3811 2015. The functional interplay between the t(9;22)-associated fusion proteins BCR/ABL and ABL/BCR in Philadelphia chromosome-positive Acute Lymphatic Leukemia. PLOS Genetics 11 (4) , e1005144. 10.1371/journal.pgen.1005144

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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 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Publisher:	Public Library of Science
ISSN:	1553-7404
Date of Acceptance:	15 March 2015
Last Modified:	17 Nov 2022 15:02
URI:	https://orca.cardiff.ac.uk/id/eprint/85879

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