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 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.
Department of Hematology, Goethe University Hospital, Frankfurt, Germany.
Anahita
A
Rafiei
Department of Hematology, Goethe University Hospital, Frankfurt, Germany.
Afsar Ali
AA
Mian
Dr. Senckenberg Institute of Pathology, Goethe University Hospital, Frankfurt, Germany.
Claudia
C
Döring
Department of Hematology, Goethe University Hospital, Frankfurt, Germany.
Anna
A
Metodieva
Department of Hematology, Goethe University Hospital, Frankfurt, Germany.
Claudia
C
Oancea
Department of Hematology, Goethe University Hospital, Frankfurt, Germany.
Frederic B
FB
Thalheimer
Dr. Senckenberg Institute of Pathology, Goethe University Hospital, Frankfurt, Germany.
Martin Leo
ML
Hansmann
Department of Hematology, Goethe University Hospital, Frankfurt, Germany.
Oliver Gerhard
OG
Ottmann
Department of Hematology, Goethe University Hospital, Frankfurt, Germany.
Martin
M
Ruthardt
D045744:Cell Line, Tumor; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D016044:Fusion Proteins, bcr-abl / Q000096:biosynthesis / Q000235:genetics*; D015973:Gene Expression Regulation, Leukemic; D006412:Hematopoietic Stem Cells / Q000473:pathology; D006801:Humans; D010677:Philadelphia Chromosome; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology; D014178:Translocation, Genetic / Q000235:genetics*
D016044:Fusion Proteins, bcr-abl