An Eμ-BCL-2 transgene facilitates leukaemogenesis by ionizing radiation

Gibbons, Deena L.; Macdonald, Denise A.; McCarthy, Keith; Cleary, Helen; Plumb, Mark; Wright, Esmond; Greaves, Mel

doi:10.1038/sj.onc.1202721

Cited by 14 publications

(15 citation statements)

References 34 publications

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“…[28][29][30][31][32] By analyzing T-cell lymphomas arising in mice with constitutional translocations involving chromosome 15, Silva et al 33 demonstrated that trisomy for bands 15D2-3 (syntenic to human 8q23-24) contributes to the development or progression (or both) of these T-cell lymphomas. This region contains the Myc and Pvt1 genes.…”

Section: Discussionmentioning

confidence: 99%

Recurring chromosomal abnormalities in leukemia inPML-RARA transgenic mice parallel human acute promyelocytic leukemia

Beau

Bitts

Davis

et al. 2002

Blood

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Acute promyelocytic leukemia (APL) is characterized by the t(15;17)(q22;q11.2), which results in the PML-RARA fusion gene. In previous studies, we demonstrated that expression of a human PML-RARA complementary DNA in murine granulocyte precursor cells initiated the development of leukemia. However, leukemogenesis by PML-RARA required additional genetic alterations. To identify genetic changes that cooperate with PML-RARA in leukemogenesis, we performed spectral karyotyping analysis of myeloid leukemias from hMRP8-PML-RARA mice (11 cases) and from mice coexpressing PML-RARA and BCL2 (8 cases). Clonal abnormalities were detected in 18 of 19 cases (95%). Recurring numerical abnormalities identified in these murine leukemias included ؉15 (15 cases, 79%); loss of a sex chromosome (12 cases, 63%); ؉8 (10 cases, 53%); ؉10 (9 cases, 47%); ؉4, ؉7, or ؉14 (8 cases each, 42%); ؉16 (7 cases, 37%); and ؉6 (5 cases, 26%). In a series of 965 patients with APL, we identified secondary abnormalities in 368 (38%). The most common recurring abnormalities were ؉8 or partial trisomy of 8q (120 patients, 12.4%) and ider(17) t(15;17) (42 patients, 4.4%). The critical consequence of ؉8 in human leukemias appears to be the gain of 8q24, which is syntenic to mouse 15. Thus, our results suggest that PML-RARA-initiated murine leukemia is associated with a defined spectrum of genetic changes, and that these secondary mutations recapitulate, in part, the cytogenetic abnormalities found in human APL. (Blood. 2002;99:2985-2991

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Section: Discussionmentioning

confidence: 99%

Recurring chromosomal abnormalities in leukemia inPML-RARA transgenic mice parallel human acute promyelocytic leukemia

Beau

Bitts

Davis

et al. 2002

Blood

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“…13 Trisomy 15 is the most frequent abnormality in murine T-cell lymphomas (40%-90%), as well as in B/myeloid leukemias arising in irradiated E-BCL2 transgenic mice. 16,17 The smallest region gained is bands 15D2-3; this region is syntenic to human 8q23-24 and contains the Myc and Pvt1 genes. 17 At present, the identity of the relevant gene(s) on human 8q is unknown; however, AMLs characterized by trisomy 8 overexpress genes on chromosome 8, suggesting that gene dosage effects mediate leukemogenesis.…”

Section: Cytogenetic Analysis Of Murine Leukemias Initiated By Pml-raramentioning

confidence: 99%

Recurring chromosomal abnormalities in leukemia in PML-RARA transgenic mice identify cooperating events and genetic pathways to acute promyelocytic leukemia

Beau

Davis

Patel

et al. 2003

Blood

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Acute promyelocytic leukemia (APL) is characterized by the PML-RARA fusion gene. To identify genetic changes that cooperate with PML-RARA, we performed spectral karyotyping analysis of myeloid leukemias from transgenic PML-RARA mice and from mice coexpressing PML-RARA and BCL2, IL3, activated IL3R, or activated FLT3. A cooperating mutation that enhanced survival (BCL2) was not sufficient to complete transformation and was associated with multiple numeric abnormalities, whereas cooperating mutations that deregulated growth and enhanced survival were associated with normal karyotypes (IL3) or simple karyotypic changes (IL3R, FLT3). Recurring abnormalities included trisomy 15 (49%), trisomy 8 (46%), and ؊X/؊Y (54%). The most common secondary abnormality in human APL is ؉8 or partial trisomy of 8q24, syntenic to mouse 15. These murine leukemias have a defined spectrum of changes that recapitulates, in part, the cytogenetic abnormalities found in human APL. Our results demonstrate that different cooperating events may generate leukemia via different pathways. (Blood.

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“…Bcl-2 overexpression has also been found to facilitate leukaemogenesis induced by ionizing radiation (Gibbons et al, 1999), presumably because mutated cells fail to die. Interestingly, young mice exposed to radiation were more at risk of developing tumours than older mice, perhaps reflecting their higher level of lymphocyte production.…”

Section: Dangerous Oncogenic Liaisons: Insights From Mouse Models Andmentioning

confidence: 99%

“…Interestingly, young mice exposed to radiation were more at risk of developing tumours than older mice, perhaps reflecting their higher level of lymphocyte production. Similarly, children exposed to radiation in Hiroshima and Nagasaki had a greater incidence of lymphoid malignancy than adults (see Gibbons et al, 1999).…”

Section: Dangerous Oncogenic Liaisons: Insights From Mouse Models Andmentioning

confidence: 99%

The Bcl-2 family: roles in cell survival and oncogenesis

2003

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An Eμ-BCL-2 transgene facilitates leukaemogenesis by ionizing radiation

Cited by 14 publications

References 34 publications

Recurring chromosomal abnormalities in leukemia inPML-RARA transgenic mice parallel human acute promyelocytic leukemia

Recurring chromosomal abnormalities in leukemia inPML-RARA transgenic mice parallel human acute promyelocytic leukemia

Recurring chromosomal abnormalities in leukemia in PML-RARA transgenic mice identify cooperating events and genetic pathways to acute promyelocytic leukemia

The Bcl-2 family: roles in cell survival and oncogenesis

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