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

Yin, Mianmian; Baslan, Timour; Walker, Robert L.; Zhu, Yuelin J.; Freeland, Amy; Matsukawa, Toshihiro; Sridharan, Sriram; Nussenzweig, André; Pruitt, Steven C.; Lowe, Scott W.; Meltzer, Paul S.; Aplan, Peter D.

doi:10.1172/jci.insight.131434

Cited by 9 publications

(26 citation statements)

References 63 publications

(80 reference statements)

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“…Placing the NP23 transgene on an Mcm2 Cre/Cre background had no effect on survival compared to Mcm2 Cre/Cre ; most mice developed an aggressive pre‐T LBL (Supporting Information Table S6). Similar to Mcm2 Cre/Cre ; NHD13 mice, 9 27% (3/11) of the Mcm2 Cre/Cre ; NP23 mice developed BCP‐ALL (Supporting Information Figure S10 and Table S6). The addition of the NP23 transgene to Mcm2 Cre/Cre ; nu / nu mice largely reversed the survival advantage seen in Mcm2 Cre/Cre ; nu / nu (median, 130.5 days vs 296.5 days, p < .001), and most Mcm2 Cre/Cre ; nu / nu ; NP23 mice developed BCP‐ALL.…”

Section: Resultsmentioning

confidence: 92%

“…Pre‐T LBL(6605/4, 6645/4, 7298/2, 6781/3, 2883, 2696, 2641, and 2869) cell lines were established from single‐cell suspensions and maintained as previously reported 9,17 …”

Section: Methodsmentioning

confidence: 99%

“…The minimal resolution of this technique is approximately 100 kb, and we previously found that most mutations identified by sparse WGS in pre-T LBL associated with Mcm2 deficiency were interstitial deletions of 100-1000 kb. 9 We defined common deletions or gains to be those that occurred in at least two samples from mice with the Mcm2 hypomorph (Mcm2 Cre/Cre ;NHD13, Mcm2 Cre/Cre ;nu/nu or Mcm2 Cre/Cre ;nu/nu;NP23). In sum, we identified 24 recurrent CNA, most commonly deletions (Supporting Information Table S8).…”

Section: Ngs Identification Of Recurrent Acquired Mutationsmentioning

confidence: 99%

“…Copy number aberrations (CNAs) were determined by sparse whole-genome sequencing (WGS), as previously described. 9 Briefly, 1 μg of genomic DNA was sonicated followed by end repair and A-tail addition and ligation of TruSeq adaptors. Libraries were pooled and sequenced, targeting 4 million reads per sample.…”

Section: Sparse Whole-genome Sequencingmentioning

confidence: 99%

“…Instead, the Mcm2 Cre/Cre ;NHD13 developed pre-T LBL at the same age as Mcm2 Cre/Cre mice. 9,12 We suspected that the highly penetrant pre-T LBL phenotype was lethal to the mice before a less aggressive malignancy could develop, thus obscuring any AML that might develop in Mcm2 Cre/Cre ;NHD13 mice. As detailed herein, we used several complementary approaches to test the hypothesis that if Mcm2 Cre/Cre mice were prevented from developing pre-T LBL, we could uncover alternate forms of malignancy in Mcm2 Cre/Cre mice.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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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.

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Section: Resultsmentioning

confidence: 92%

“…Pre‐T LBL(6605/4, 6645/4, 7298/2, 6781/3, 2883, 2696, 2641, and 2869) cell lines were established from single‐cell suspensions and maintained as previously reported 9,17 …”

Section: Methodsmentioning

confidence: 99%

Section: Ngs Identification Of Recurrent Acquired Mutationsmentioning

confidence: 99%

Section: Sparse Whole-genome Sequencingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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Clinical and molecular consequences of fusion genes in myeloid malignancies

Matsukawa

Aplan

2020

Stem Cells

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Leukemias are heterogeneous diseases characterized by aberrant hematopoietic stem and progenitor cells (HSPCs). Oncogenic fusion genes and proteins, produced via gross chromosomal rearrangements, such as chromosomal translocation, insertion, and inversion, play important roles in hematologic malignancies. These oncoproteins alter fundamental cellular properties, such as self‐renewal, differentiation, and proliferation, and confer leukemogenic potential to HSPCs. In addition to providing fundamental insights into the process of leukemic transformation, these fusion genes provide targets for treatment and monitoring of myeloid leukemias. Furthermore, new technologies such as next‐generation sequencing have allowed additional insights into the nature of leukemic fusion genes. In this review, we discuss the history, biologic effect, and clinical impact of fusion genes in the field of myeloid leukemias.

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Unwinding Helicase MCM Functionality for Diagnosis and Therapeutics of Replication Abnormalities Associated with Cancer: A Review

Radhakrishnan,

Gangopadhyay,

Sharma

et al. 2024

Mol Diagn Ther

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

Cited by 9 publications

References 63 publications

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

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

Clinical and molecular consequences of fusion genes in myeloid malignancies

Unwinding Helicase MCM Functionality for Diagnosis and Therapeutics of Replication Abnormalities Associated with Cancer: A Review

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