Convergent genetic aberrations in murine and human T lineage acute lymphoblastic leukemias

• DOI: 10.1371/journal.pgen.1008168
• Publication Date: 2019-06-14T17:28:42Z
• Authors: Benjamin J. Huang; Anica M. Wandler; Lauren K. Meyer; Monique Dail; Anneleen Daemen; Deepak Sampath; Qing Li; Xinyue Wang; Jasmine C. Wong; Joy Nakitandwe; James R. Downing; Jinghui Zhang; Barry S. Taylor; Kevin Shannon
• Keywords: Insertional mutagenesis; Lineage (genetic)

The lack of predictive preclinical models is a fundamental barrier to translating knowledge about the molecular pathogenesis cancer into improved therapies. Insertional mutagenesis (IM) in mice robust strategy for generating malignancies that recapitulate extensive inter- and intra-tumoral genetic heterogeneity found advanced human cancers. While central role "driver" viral insertions IM aberrantly increase expression proto-oncogenes or disrupt tumor suppressors has been appreciated many years, contributions cooperating somatic mutations large chromosomal alterations tumorigenesis are largely unknown. Integrated genomic studies T lineage acute lymphoblastic leukemias (T-ALLs) generated by wild-type (WT) Kras mutant reveal frequent point other recurrent non-insertional also occur T-ALL. These sensitive specific markers defining clonal dynamics identifying candidate resistance mechanisms relapse after an initial therapeutic response. Primary cancers initiated resistant clones emerge during vivo treatment close key gaps existing models, platforms investigating efficacy new therapies elucidating how drug exposure shapes evolution patterns resistance.