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Background  t(9;22) is a balanced translocation, and the chromosome 22 breakpoints (Philadelphia chromosome – Ph + ) determine formation of different fusion genes that are associated with either Ph +  acute lymphatic leukemia (Ph +  ALL) or chronic myeloid leukemia (CML). The “minor” breakpoint in Ph +  ALL encodes p185  BCR/ABL   from der22 and p96  ABL/BCR   from der9. The “major” breakpoint in CML encodes p210  BCR/ABL   and p40  ABL/BCR  . Herein, we investigated the leukemogenic potential of the der9-associated p96  ABL/BCR   and p40  ABL/BCR   fusion proteins and their roles in the lineage commitment of hematopoietic stem cells in comparison to BCR/ABL.    Methodology  All t(9;22) derived proteins were retrovirally expressed in murine hematopoietic stem cells (SL cells) and human umbilical cord blood cells (UCBC). Stem cell potential was determined by replating efficiency, colony forming - spleen and competitive repopulating assays. The leukemic potential of the ABL/BCR fusion proteins was assessed by in a transduction/transplantation model. Effects on the lineage commitment and differentiation were investigated by culturing the cells under conditions driving either myeloid or lymphoid commitment. Expression of key factors of the B-cell differentiation and components of the preB-cell receptor were determined by qRT-PCR.    Principal Findings  Both p96  ABL/BCR   and p40  ABL/BCR   increased proliferation of early progenitors and the short term stem cell capacity of SL-cells and exhibited own leukemogenic potential. Interestingly, BCR/ABL gave origin exclusively to a myeloid phenotype independently from the culture conditions whereas p96  ABL/BCR   and to a minor extent p40  ABL/BCR   forced the B-cell commitment of SL-cells and UCBC.    Conclusions/Significance  Our here presented data establish the reciprocal ABL/BCR fusion proteins as second oncogenes encoded by the t(9;22) in addition to BCR/ABL and suggest that ABL/BCR contribute to the determination of the leukemic phenotype through their influence on the lineage commitment.

Reciprocal t(9;22) ABL/BCR Fusion Proteins: Leukemogenic Potential and Effects on B Cell Commitment