Mice with a “deletor” phenotype allow identification of tumor suppressor genes and oncogenic fusion genes in lymphoid malignancies

Authors

• MM Yin
• TB Baslan
• A Freeland
• SC Pruitt
• PD Aplan

Abstract

Mice that are homozygous for a deficiency allele of the DNA replication factor minichromosome maintenance protein 2 (designated Mcm2def) are born viable and are healthy for the first 2 months of life. Beginning at three months, these mice develop precursor T-cell lymphoblastic leukemia/lymphoma (pre-T LBL). Copy number aberration (CNA) analysis showed that these pre-T LBL samples had 8-14 small (100-1000 kb) interstitial deletions per sample. Remarkably, all mice had two or more deletions that encompassed genes known to be relevant for human pre-T LBL, including Pten, Cdkn1a, Tcf3, and Tcf12. Mice that express a NUP98-HOXD13 (NHD13) transgene develop a wide array of leukemias, most commonly myeloid, less commonly T-cell, and, rarely, B-lineage. To identify myeloid tumor suppressor genes, we crossed the NHD13 transgene onto the Mcm2def background. All Mcm2def:NHD13+ mice developed DP(CD4+CD8+)pre-T LBL by 3 months of age, reflecting the highly penetrant nature of the Mcm2def phenotype. None of the Mcm2def:NHD13+ mice developed myeloid leukemia. Surprisingly, approximately 30% of the Mcm2def:NHD13+ mice developed concurrent B-cell precursor acute lymphoblastic leukemia (BCP-ALL) and pre-T LBL. The thymus was typically infiltrated with pre-T LBL cells, whereas the bone marrow and spleen were infiltrated with BCP-ALL cells, characterized by IGH clonal VDJ rearrangement and CD19 staining. Parenchymal organs (lung, kidney, liver) were variably infiltrated with pre-T LBL, BCP-ALL, or both. CNA analysis showed that the pre-T LBL were characterized by short deletions including Pten, CDkn1a, Tcf3, and Tcf12 deletions, similar to the Mcm2def pre-T LBL, whereas the BCP-ALL were characterized by homozygous or heterozygous deletions including Pax5 and a 400 kb region encompassing Cebpb and Ptpn1, and amplifications including NUP214-ABL1 fusion gene. There were no shared deletions present in both BCP-ALL and pre-T LBL from the same mouse, indicating that the BCP-ALL and pre-T LBL arose independently, and not from a common precursor. The Mcm2def:NHD13+ BCP-ALL mouse model was validated by the high frequency (5/7 samples) of acquired Pax5 deletions and amplification of NUP214-ABL1 fusion gene in the BCP-ALL samples , which have been implicated in human BCP-ALL . In general, Mcm2def:NHD13+ mouse model could be used to high resolution detection of BCP-ALL tumor suppressor genes and pathway. The finding of Cebpb/Ptpn1 deletions (5/7 samples) and other genes deletions or amplifications suggests an unanticipated role of either Cebpb or Ptpn1 and other genes in BCP-ALL.

Scientific Focus Area: Cancer Biology

This page was last updated on Friday, March 26, 2021