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

Authors

• MM Yin
• T 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) develop precursor T-cell lymphoblastic leukemia/lymphoma (pre-T LBL) at three months. Copy number aberration (CNA) analysis showed that each pre-T LBL sample had 8-14 small interstitial deletions that encompassed genes associated with human pre-T LBL. NUP98-HOXD13 (NHD13) transgenic mice 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 CD4+CD8+pre-T LBL. However, 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. Thymus was infiltrated with pre-T LBL cells, whereas bone marrow and spleen were infiltrated with BCP-ALL cells. CNA analysis showed that pre-T LBL were characterized by short deletions, similar to the Mcm2def pre-T LBL, whereas the BCP-ALL were characterized by deletions including Pax5, Cebpb and Ptpn1, and amplifications including recurrent 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. Mcm2def:NHD13+ BCP-ALL mouse model was validated by the high frequency of acquired Pax5 deletions and NUP214-ABL1 fusion gene, both of which are commonly detected in human BCP-ALL . Furthermore, the finding of Cebpb/Ptpn1 deletions suggests an unanticipated role of either Cebpb or Ptpn1 in BCP-ALL.

Scientific Focus Area: Cancer Biology

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