A unique mutator phenotype reveals complementary oncogenic lesions leading to acute leukemia Journal Article
| Authors: | Yin, M.; Baslan, T.; Walker, R. L.; Zhu, Y. J.; Freeland, A.; Matsukawa, T.; Sridharan, S.; Nussenzweig, A.; Pruitt, S. C.; Lowe, S. W.; Meltzer, P. S.; Aplan, P. D. |
| Article Title: | A unique mutator phenotype reveals complementary oncogenic lesions leading to acute leukemia |
| Abstract: | Mice homozygous for a hypomorphic allele of DNA replication factor minichromosome maintenance protein 2 (designated Mcm2cre/cre) develop precursor T cell lymphoblastic leukemia/ lymphoma (pre-T LBL) with 4 32 small interstitial deletions per tumor. Mice that express a NUP98-HOXD13 (NHD13) transgene develop multiple types of leukemia, including myeloid and T and B lymphocyte. All Mcm2cre/cre NHD13+ mice develop pre-T LBL, and 26% develop an unrelated, concurrent B cell precursor acute lymphoblastic leukemia (BCP-ALL). Copy number alteration (CNA) analysis demonstrated that pre-T LBLs were characterized by homozygous deletions of Pten and Tcf3 and partial deletions of Notch1 leading to Notch1 activation. In contrast, BCP-ALLs were characterized by recurrent deletions involving Pax5 and Ptpn1 and copy number gain of Abl1 and Nup214 resulting in a Nup214-Abl1 fusion. We present a model in which Mcm2 deficiency leads to replicative stress, DNA double strand breaks (DSBs), and resultant CNAs due to errors in DNA DSB repair. CNAs that involve critical oncogenic pathways are then selected in vivo as malignant lymphoblasts because of a fitness advantage. Some CNAs, such as those involving Abl1 and Notch1, represent attractive targets for therapy. © 2019, American Society for Clinical Investigation. |
| Keywords: | controlled study; gene deletion; cancer growth; nonhuman; dna replication; animal cell; mouse; allele; animal tissue; dna repair; gene expression; animal experiment; animal model; cohort analysis; in vivo study; acute lymphoblastic leukemia; mutator gene; b cell lymphoma; gene activation; acute leukemia; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; carcinogenicity; gene fusion; transgene; double stranded dna break; t cell leukemia; notch1 receptor; myeloid leukemia; molecularly targeted therapy; copy number variation; pten gene; minichromosome maintenance protein 2; protein tyrosine phosphatase 1b; transcription factor pax5; human; article; pax5 gene; transcription factor 7 like 1; lymphocytic lymphoma; notch1 gene; tcf3 gene; abl1 gene; nup214 abl1 gene; nup214 gene; nup98 hoxd13 gene; ptpn1 gene |
| Journal Title: | JCI Insight |
| Volume: | 4 |
| Issue: | 23 |
| ISSN: | 2379-3708 |
| Publisher: | Amer Soc Clinical Investigation Inc |
| Date Published: | 2019-12-05 |
| Start Page: | e131434 |
| Language: | English |
| DOI: | 10.1172/jci.insight.131434 |
| PUBMED: | 31622281 |
| PROVIDER: | scopus |
| PMCID: | PMC6962024 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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