title: Reciprocal t(9;22) ABL/BCR fusion proteins: leukemogenic potential and effects on B cell commitment.
abstract: 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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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
  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.
authors.affiliation: Department of Hematology, Laboratory for Tumor Stem Cell Biology, Goethe University, Frankfurt, Germany.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Zheng
authors.forename: Claudia
authors.initials: C
authors.lastname: Oancea
authors.forename: Reinhard
authors.initials: R
authors.lastname: Henschler
authors.forename: Malcolm A S
authors.initials: MA
authors.lastname: Moore
authors.forename: Martin
authors.initials: M
authors.lastname: Ruthardt
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology*; D002454:Cell Differentiation; D002892:Chromosomes, Human, Pair 22; D002899:Chromosomes, Human, Pair 9; D005312:Fetal Blood / Q000166:cytology; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics*; D051379:Mice; D012190:Retroviridae / Q000235:genetics; D013234:Stem Cells / Q000166:cytology; D014178:Translocation, Genetic; D020298:U937 Cells
chemical_list: D016044:Fusion Proteins, bcr-abl