A unique mutator phenotype reveals complementary oncogenic lesions leading to acute leukemia

JCI Insight. 2019 Dec 5;4(23):e131434. doi: 10.1172/jci.insight.131434.

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.

Keywords: Cancer; Genetic instability; Genetics; Hematology; Leukemias.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Carcinogenesis / genetics*
  • Carcinogenesis / metabolism*
  • Carcinogenesis / pathology
  • Cell Line, Tumor
  • DNA Copy Number Variations
  • Disease Models, Animal
  • Gene Expression Regulation, Neoplastic
  • Homeodomain Proteins / genetics
  • Humans
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / metabolism*
  • Leukemia, Myeloid, Acute / pathology
  • Mice
  • Mice, Inbred C57BL
  • Minichromosome Maintenance Complex Component 2 / genetics
  • Minichromosome Maintenance Complex Component 2 / metabolism
  • Nuclear Pore Complex Proteins / genetics
  • Nuclear Pore Complex Proteins / metabolism
  • PAX5 Transcription Factor / metabolism
  • Phenotype*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism
  • Proto-Oncogene Proteins c-abl / metabolism
  • Receptor, Notch1 / genetics
  • Receptor, Notch1 / metabolism
  • Spleen / pathology
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcriptome

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Homeodomain Proteins
  • Hoxd13 protein, mouse
  • Mcm2 protein, mouse
  • Notch1 protein, mouse
  • Nuclear Pore Complex Proteins
  • Nup214 protein, mouse
  • PAX5 Transcription Factor
  • Pax5 protein, mouse
  • Receptor, Notch1
  • Tcf3 protein, mouse
  • Transcription Factors
  • nuclear pore complex protein 98
  • Proto-Oncogene Proteins c-abl
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Ptpn1 protein, mouse
  • Minichromosome Maintenance Complex Component 2