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 d...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2015-04-01
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| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC4412790?pdf=render |
| _version_ | 1828815356971450368 |
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| author | Anahita Rafiei Afsar Ali Mian Claudia Döring Anna Metodieva Claudia Oancea Frederic B Thalheimer Martin Leo Hansmann Oliver Gerhard Ottmann Martin Ruthardt |
| author_facet | Anahita Rafiei Afsar Ali Mian Claudia Döring Anna Metodieva Claudia Oancea Frederic B Thalheimer Martin Leo Hansmann Oliver Gerhard Ottmann Martin Ruthardt |
| author_sort | Anahita Rafiei |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-12T10:42:01Z |
| format | Article |
| id | doaj.art-e656123223284eafa41f1d7b430b3911 |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-12-12T10:42:01Z |
| publishDate | 2015-04-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-e656123223284eafa41f1d7b430b39112022-12-22T00:27:01ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042015-04-01114e100514410.1371/journal.pgen.1005144The functional interplay between the t(9;22)-associated fusion proteins BCR/ABL and ABL/BCR in Philadelphia chromosome-positive acute lymphatic leukemia.Anahita RafieiAfsar Ali MianClaudia DöringAnna MetodievaClaudia OanceaFrederic B ThalheimerMartin Leo HansmannOliver Gerhard OttmannMartin RuthardtThe 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.http://europepmc.org/articles/PMC4412790?pdf=render |
| spellingShingle | Anahita Rafiei Afsar Ali Mian Claudia Döring Anna Metodieva Claudia Oancea Frederic B Thalheimer Martin Leo Hansmann Oliver Gerhard Ottmann Martin Ruthardt 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 |
| title | The functional interplay between the t(9;22)-associated fusion proteins BCR/ABL and ABL/BCR in Philadelphia chromosome-positive acute lymphatic leukemia. |
| title_full | The functional interplay between the t(9;22)-associated fusion proteins BCR/ABL and ABL/BCR in Philadelphia chromosome-positive acute lymphatic leukemia. |
| title_fullStr | The functional interplay between the t(9;22)-associated fusion proteins BCR/ABL and ABL/BCR in Philadelphia chromosome-positive acute lymphatic leukemia. |
| title_full_unstemmed | The functional interplay between the t(9;22)-associated fusion proteins BCR/ABL and ABL/BCR in Philadelphia chromosome-positive acute lymphatic leukemia. |
| title_short | The functional interplay between the t(9;22)-associated fusion proteins BCR/ABL and ABL/BCR in Philadelphia chromosome-positive acute lymphatic leukemia. |
| title_sort | functional interplay between the t 9 22 associated fusion proteins bcr abl and abl bcr in philadelphia chromosome positive acute lymphatic leukemia |
| url | http://europepmc.org/articles/PMC4412790?pdf=render |
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