Mcm2 hypomorph leads to acute leukemia or hematopoietic stem cell failure, dependent on genetic context Journal Article
| Authors: | Matsukawa, T.; Yin, M.; Baslan, T.; Chung, Y. J.; Cao, D.; Bertoli, R.; Zhu, Y. J.; Walker, R. L.; Freeland, A.; Knudsen, E.; Lowe, S. W.; Meltzer, P. S.; Aplan, P. D. |
| Article Title: | Mcm2 hypomorph leads to acute leukemia or hematopoietic stem cell failure, dependent on genetic context |
| Abstract: | 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 Mcm2Cre ) 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 Mcm2Cre/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 Mcm2Cre 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 Mcm2Cre/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 Mcm2Cre/Cre hypomorph can induce hematopoietic dysfunction via hematopoietic stem cell failure as well as a "deletor" phenotype affecting known or suspected tumor suppressor genes. © 2022 Federation of American Societies for Experimental Biology. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA. |
| Keywords: | genetics; mutation; leukemia, myeloid, acute; dna replication; mouse; animal; metabolism; animals; mice; transcription factor; transcription factors; tumor suppressor gene; hematopoietic stem cells; hematopoietic stem cell; repressor protein; repressor proteins; acute myeloid leukemia; bone marrow failure; mcm2; b-cell precursor acute lymphoblastic leukemia; dna stress; bcor protein, mouse |
| Journal Title: | FASEB Journal |
| Volume: | 36 |
| Issue: | 9 |
| ISSN: | 0892-6638 |
| Publisher: | Federation of American Societies for Experimental Biology |
| Date Published: | 2022-09-01 |
| Start Page: | e22430 |
| Language: | English |
| DOI: | 10.1096/fj.202200061RR |
| PUBMED: | 35920299 |
| PROVIDER: | scopus |
| PMCID: | PMC9377154 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 September 2022 -- Source: Scopus |
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