| First Author | Matsukawa T | Year | 2022 |
| Journal | FASEB J | Volume | 36 |
| Issue | 9 | Pages | e22430 |
| PubMed ID | 35920299 | Mgi Jnum | J:329886 |
| Mgi Id | MGI:7355012 | Doi | 10.1096/fj.202200061RR |
| Citation | Matsukawa T, et al. (2022) Mcm2 hypomorph leads to acute leukemia or hematopoietic stem cell failure, dependent on genetic context. FASEB J 36(9):e22430 |
| abstractText | 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. |
