PAX5 is a tumor suppressor in mouse mutagenesis models of acute lymphoblastic leukemia
Alterations of genes encoding transcriptional regulators of lymphoid development are a hallmark of B-progenitor acute lymphoblastic leukemia (B-ALL) and most commonly involve PAX5, encoding the DNA-binding transcription factor paired-box 5. The majority of PAX5 alterations in ALL are heterozygous, a...
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| Published in: | Blood Vol. 125; no. 23; p. 3609 |
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| Main Authors: | , , , , , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
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United States
04.06.2015
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| ISSN: | 1528-0020, 1528-0020 |
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| Abstract | Alterations of genes encoding transcriptional regulators of lymphoid development are a hallmark of B-progenitor acute lymphoblastic leukemia (B-ALL) and most commonly involve PAX5, encoding the DNA-binding transcription factor paired-box 5. The majority of PAX5 alterations in ALL are heterozygous, and key PAX5 target genes are expressed in leukemic cells, suggesting that PAX5 may be a haploinsufficient tumor suppressor. To examine the role of PAX5 alterations in leukemogenesis, we performed mutagenesis screens of mice heterozygous for a loss-of-function Pax5 allele. Both chemical and retroviral mutagenesis resulted in a significantly increased penetrance and reduced latency of leukemia, with a shift to B-lymphoid lineage. Genomic profiling identified a high frequency of secondary genomic mutations, deletions, and retroviral insertions targeting B-lymphoid development, including Pax5, and additional genes and pathways mutated in ALL, including tumor suppressors, Ras, and Janus kinase-signal transducer and activator of transcription signaling. These results show that in contrast to simple Pax5 haploinsufficiency, multiple sequential alterations targeting lymphoid development are central to leukemogenesis and contribute to the arrest in lymphoid maturation characteristic of ALL. This cross-species analysis also validates the importance of concomitant alterations of multiple cellular growth, signaling, and tumor suppression pathways in the pathogenesis of B-ALL. |
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| AbstractList | Alterations of genes encoding transcriptional regulators of lymphoid development are a hallmark of B-progenitor acute lymphoblastic leukemia (B-ALL) and most commonly involve PAX5, encoding the DNA-binding transcription factor paired-box 5. The majority of PAX5 alterations in ALL are heterozygous, and key PAX5 target genes are expressed in leukemic cells, suggesting that PAX5 may be a haploinsufficient tumor suppressor. To examine the role of PAX5 alterations in leukemogenesis, we performed mutagenesis screens of mice heterozygous for a loss-of-function Pax5 allele. Both chemical and retroviral mutagenesis resulted in a significantly increased penetrance and reduced latency of leukemia, with a shift to B-lymphoid lineage. Genomic profiling identified a high frequency of secondary genomic mutations, deletions, and retroviral insertions targeting B-lymphoid development, including Pax5, and additional genes and pathways mutated in ALL, including tumor suppressors, Ras, and Janus kinase-signal transducer and activator of transcription signaling. These results show that in contrast to simple Pax5 haploinsufficiency, multiple sequential alterations targeting lymphoid development are central to leukemogenesis and contribute to the arrest in lymphoid maturation characteristic of ALL. This cross-species analysis also validates the importance of concomitant alterations of multiple cellular growth, signaling, and tumor suppression pathways in the pathogenesis of B-ALL. Alterations of genes encoding transcriptional regulators of lymphoid development are a hallmark of B-progenitor acute lymphoblastic leukemia (B-ALL) and most commonly involve PAX5, encoding the DNA-binding transcription factor paired-box 5. The majority of PAX5 alterations in ALL are heterozygous, and key PAX5 target genes are expressed in leukemic cells, suggesting that PAX5 may be a haploinsufficient tumor suppressor. To examine the role of PAX5 alterations in leukemogenesis, we performed mutagenesis screens of mice heterozygous for a loss-of-function Pax5 allele. Both chemical and retroviral mutagenesis resulted in a significantly increased penetrance and reduced latency of leukemia, with a shift to B-lymphoid lineage. Genomic profiling identified a high frequency of secondary genomic mutations, deletions, and retroviral insertions targeting B-lymphoid development, including Pax5, and additional genes and pathways mutated in ALL, including tumor suppressors, Ras, and Janus kinase-signal transducer and activator of transcription signaling. These results show that in contrast to simple Pax5 haploinsufficiency, multiple sequential alterations targeting lymphoid development are central to leukemogenesis and contribute to the arrest in lymphoid maturation characteristic of ALL. This cross-species analysis also validates the importance of concomitant alterations of multiple cellular growth, signaling, and tumor suppression pathways in the pathogenesis of B-ALL.Alterations of genes encoding transcriptional regulators of lymphoid development are a hallmark of B-progenitor acute lymphoblastic leukemia (B-ALL) and most commonly involve PAX5, encoding the DNA-binding transcription factor paired-box 5. The majority of PAX5 alterations in ALL are heterozygous, and key PAX5 target genes are expressed in leukemic cells, suggesting that PAX5 may be a haploinsufficient tumor suppressor. To examine the role of PAX5 alterations in leukemogenesis, we performed mutagenesis screens of mice heterozygous for a loss-of-function Pax5 allele. Both chemical and retroviral mutagenesis resulted in a significantly increased penetrance and reduced latency of leukemia, with a shift to B-lymphoid lineage. Genomic profiling identified a high frequency of secondary genomic mutations, deletions, and retroviral insertions targeting B-lymphoid development, including Pax5, and additional genes and pathways mutated in ALL, including tumor suppressors, Ras, and Janus kinase-signal transducer and activator of transcription signaling. These results show that in contrast to simple Pax5 haploinsufficiency, multiple sequential alterations targeting lymphoid development are central to leukemogenesis and contribute to the arrest in lymphoid maturation characteristic of ALL. This cross-species analysis also validates the importance of concomitant alterations of multiple cellular growth, signaling, and tumor suppression pathways in the pathogenesis of B-ALL. |
| Author | Roberts, Kathryn G Song, Guangchun Janke, Laura Downing, James R Wei, Lei Cheng, Jinjun Payne-Turner, Debbie de Ridder, Jeroen Schulman, Brenda Rust, Alistair G Qu, Chunxu Zhang, Jinghui Ma, Jing Adams, David J Dang, Jinjun van der Weyden, Louise Wu, Gang Huether, Robert G Su, Xiaoping Mullighan, Charles G |
| Author_xml | – sequence: 1 givenname: Jinjun surname: Dang fullname: Dang, Jinjun organization: Department of Pathology, St Jude Children's Research Hospital, Memphis, TN – sequence: 2 givenname: Lei surname: Wei fullname: Wei, Lei organization: Department of Pathology, St Jude Children's Research Hospital, Memphis, TN – sequence: 3 givenname: Jeroen surname: de Ridder fullname: de Ridder, Jeroen organization: Faculty of Electrical Engineering, Mathematics and Computer Science, Delft Bioinformatics Laboratory, Delft University of Technology, Delft, The Netherlands – sequence: 4 givenname: Xiaoping surname: Su fullname: Su, Xiaoping organization: Department of Pathology, St Jude Children's Research Hospital, Memphis, TN – sequence: 5 givenname: Alistair G surname: Rust fullname: Rust, Alistair G organization: Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom – sequence: 6 givenname: Kathryn G surname: Roberts fullname: Roberts, Kathryn G organization: Department of Pathology, St Jude Children's Research Hospital, Memphis, TN – sequence: 7 givenname: Debbie surname: Payne-Turner fullname: Payne-Turner, Debbie organization: Department of Pathology, St Jude Children's Research Hospital, Memphis, TN – sequence: 8 givenname: Jinjun surname: Cheng fullname: Cheng, Jinjun organization: Department of Pathology, St Jude Children's Research Hospital, Memphis, TN – sequence: 9 givenname: Jing surname: Ma fullname: Ma, Jing organization: Department of Pathology, St Jude Children's Research Hospital, Memphis, TN – sequence: 10 givenname: Chunxu surname: Qu fullname: Qu, Chunxu organization: Department of Computational Biology, St Jude Children's Research Hospital, Memphis, TN; and – sequence: 11 givenname: Gang surname: Wu fullname: Wu, Gang organization: Department of Computational Biology, St Jude Children's Research Hospital, Memphis, TN; and – sequence: 12 givenname: Guangchun surname: Song fullname: Song, Guangchun organization: Department of Pathology, St Jude Children's Research Hospital, Memphis, TN – sequence: 13 givenname: Robert G surname: Huether fullname: Huether, Robert G organization: Department of Structural Biology, St Jude Children's Research Hospital, Memphis, TN – sequence: 14 givenname: Brenda surname: Schulman fullname: Schulman, Brenda organization: Department of Structural Biology, St Jude Children's Research Hospital, Memphis, TN – sequence: 15 givenname: Laura surname: Janke fullname: Janke, Laura organization: Department of Pathology, St Jude Children's Research Hospital, Memphis, TN – sequence: 16 givenname: Jinghui surname: Zhang fullname: Zhang, Jinghui organization: Department of Computational Biology, St Jude Children's Research Hospital, Memphis, TN; and – sequence: 17 givenname: James R surname: Downing fullname: Downing, James R organization: Department of Pathology, St Jude Children's Research Hospital, Memphis, TN – sequence: 18 givenname: Louise surname: van der Weyden fullname: van der Weyden, Louise organization: Department of Structural Biology, St Jude Children's Research Hospital, Memphis, TN – sequence: 19 givenname: David J surname: Adams fullname: Adams, David J organization: Department of Structural Biology, St Jude Children's Research Hospital, Memphis, TN – sequence: 20 givenname: Charles G orcidid: 0000-0002-1871-1850 surname: Mullighan fullname: Mullighan, Charles G organization: Department of Pathology, St Jude Children's Research Hospital, Memphis, TN |
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| SubjectTerms | Animals Gene Deletion Mice Mice, Mutant Strains Neoplasms, Experimental - genetics Neoplasms, Experimental - metabolism Neoplasms, Experimental - pathology PAX5 Transcription Factor - genetics PAX5 Transcription Factor - metabolism Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology Tumor Suppressor Proteins - genetics Tumor Suppressor Proteins - metabolism |
| Title | PAX5 is a tumor suppressor in mouse mutagenesis models of acute lymphoblastic leukemia |
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