Mcm2 hypomorph leads to acute leukemia or hematopoietic stem cell failure, dependent on genetic context

Minichromosome maintenance proteins (Mcm2-7) form a hexameric complex that unwinds DNA ahead of a replicative fork. The deficiency of Mcm proteins leads to replicative stress and consequent genomic instability. Mice with a germline insertion of a Cre cassette into the 3 ' UTR of the Mcm2 gene (designated Mcm2(Cre)) have decreased Mcm2 expression and invariably develop precursor T-cell lymphoblastic leukemia/lymphoma (pre-T LBL), due to 100-1000 kb deletions involving important tumor suppressor genes. To determine whether mice that were protected from pre-T LBL would develop non-T-cell malignancies, we used two approaches. Mice engrafted with Mcm2(Cre/Cre) Lin(-)Sca-1(+)Kit(+) hematopoietic stem/progenitor cells did not develop hematologic malignancy; however, these mice died of hematopoietic stem cell failure by 6 months of age. Placing the Mcm2(Cre) allele onto an athymic nu/nu background completely prevented pre-T LBL and extended survival of these mice three-fold (median 296.5 vs. 80.5 days). Ultimately, most Mcm2(Cre/Cre);nu/nu mice developed B-cell precursor acute lymphoblastic leukemia (BCP-ALL). We identified recurrent deletions of 100-1000 kb that involved genes known or suspected to be involved in BCP-ALL, including Pax5, Nf1, Ikzf3, and Bcor. Moreover, whole-exome sequencing identified recurrent mutations of genes known to be involved in BCP-ALL progression, such as Jak1/Jak3, Ptpn11, and Kras. These findings demonstrate that an Mcm2(Cre/Cre) hypomorph can induce hematopoietic dysfunction via hematopoietic stem cell failure as well as a deletor phenotype affecting known or suspected tumor suppressor genes.

Automated summary

The deficiency of Mcm2 proteins leads to genomic instability and cancer. In this study, mice with decreased expression of Mcm2 developed precursor T-cell lymphoblastic leukemia/lymphoma. However, when these mice were engrafted onto athymic nu/nu mice, pre-T LBL was prevented but B-cell precursor acute lymphoblastic leukemia occurred instead.