Reciprocal t (9;22) ABL/BCR fusion proteins: Leukemogenic potential and effects on B cell commitment Journal Article
| Authors: | Zheng, X.; Oancea, C.; Henschler, R.; Moore, M. A. S.; Ruthardt, M. |
| Article 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<sup>+</sup>) determine formation of different fusion genes that are associated with either Ph<sup>+</sup> acute lymphatic leukemia (Ph<sup>+</sup> ALL) or chronic myeloid leukemia (CML). The "minor" breakpoint in Ph<sup>+</sup> ALL encodes p185<sup>BCR/ABL</sup> from der22 and p96<sup>ABL/BCR</sup> from der9. The "major" breakpoint in CML encodes p210<sup>BCR/ABL</sup> and p40<sup>ABL/BCR</sup>. Herein, we investigated the leukemogenic potential of the der9-associated p96<sup>ABL/BCR</sup> and p40<sup>ABL/BCR</sup> 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<sup>ABL/BCR</sup> and p40<sup>ABL/BCR</sup> 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<sup>ABL/BCR</sup> and to a minor extent p40<sup>ABL/BCR</sup> 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. © 2009 Zheng et al. |
| Keywords: | controlled study; protein expression; gene translocation; genetics; nonhuman; protein function; cell proliferation; animal cell; mouse; animal; cytology; animals; mice; reverse transcription polymerase chain reaction; animal experiment; chromosomes, human, pair 9; cell differentiation; abelson kinase; chronic myeloid leukemia; b lymphocyte; b-lymphocytes; stem cell; fetal blood; fetus blood; cell culture; quantitative analysis; hematopoietic stem cells; murinae; stem cells; umbilical cord blood; translocation, genetic; hematopoietic stem cell; bcr abl protein; leukemia, myelogenous, chronic, bcr-abl positive; myeloid progenitor cell; fusion proteins, bcr-abl; retrovirus; retroviridae; pre b lymphocyte; reciprocal chromosome translocation; protein p185; protein p40; chromosome 22; colony forming cell; cell strain u937; chromosome 9; chromosomes, human, pair 22; u937 cells |
| Journal Title: | PLoS ONE |
| Volume: | 4 |
| Issue: | 10 |
| ISSN: | 1932-6203 |
| Publisher: | Public Library of Science |
| Date Published: | 2009-10-30 |
| Start Page: | e7661 |
| Language: | English |
| DOI: | 10.1371/journal.pone.0007661 |
| PUBMED: | 19876398 |
| PROVIDER: | scopus |
| PMCID: | PMC2764858 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 30 November 2010" - "Art. No.: e7661" - "Source: Scopus" |
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