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Recurring chromosomal abnormalities in leukemia in PML-RARA transgenic mice parallel human acute promyelocytic
Michelle M Le Beau1, Sheila Bitts, Elizabeth M Davis
1Section of Hematology/Oncology, University of Chicago, Illinois 60637, USA. mlebeau@medicine.bsd.uchicago.edu
Abstract:
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.
Insights
Genetic alterations cooperate with the PML-RARA fusion gene to drive acute promyelocytic leukemia (APL) development. Secondary mutations in mouse models partially mirror cytogenetic abnormalities observed in human APL patients.
Area of Science:
- Hematology
- Cancer Genetics
- Molecular Biology
Background:
- Acute promyelocytic leukemia (APL) is defined by the t(15;17) translocation, creating the PML-RARA fusion gene.
- Previous research established that PML-RARA expression in murine granulocyte precursors can initiate leukemia, but requires additional genetic changes.
Purpose of the Study:
- To identify genetic alterations that cooperate with PML-RARA in leukemogenesis.
- To compare genetic changes in murine models with human APL cytogenetics.
Main Methods:
- Spectral karyotyping analysis of myeloid leukemias in PML-RARA transgenic mice.
- Analysis of secondary genetic abnormalities in a cohort of 965 human APL patients.
Main Results:
- Clonal abnormalities were detected in 95% of murine leukemias, with common numerical changes including +15, loss of sex chromosome, and +8.
- In human APL, secondary abnormalities occurred in 38% of patients, with +8/trisomy 8q and ider(17) being most frequent.
- Gain of 8q24 in human leukemia is syntenic to mouse chromosome 15, suggesting conserved mechanisms.
Conclusions:
- PML-RARA-initiated murine leukemia exhibits a specific spectrum of genetic changes.
- These secondary mutations in mice partially recapitulate the cytogenetic abnormalities found in human APL.
- The findings highlight conserved genetic cooperation in APL pathogenesis across species.