TP53 mutations are observed in 5 to10% of de novo AML cases with dismal disease prognosis and response to therapy. We found that MDM2 loss of heterozygosity (MDM2 LOH) in AML was always concomitant with TP53 missense mutations (log2 odds ratio>3, p<.001), and not TP53 deletions or truncations whereas in lymphomas, MDM2 LOH and TP53 mutations were mutually exclusive. To understand the functional association of MDM2 LOH and TP53 mutation in AML, we generated a conditional somatic Trp53 mutant AML mouse by combining a Trp53R172H mutation with Mdm2 haploinsufficiency in hematopoietic cells using Vav-cre transgenic mice combined with RosamTmG (mTmG) allele as tracing reporter. The conditional mutant Trp53 allele used in this study harbored a R172H mutation downstream of a wildtype Trp53 cDNA flanked by loxP sites (Trp53wm-R172H) so that the expression of the wildtype Trp53 was preserved before the recombination. Mouse cohorts were generated to harbor one Trp53wm-R172H allele and a Trp53fl or were homozygous for the floxed Trp53 allele (Trp53fl/fl). The expression of Cre in hematopoietic stem cells resulted in heterozygous deletion of Mdm2 and conversion of WT Trp53 to Trp53R172, which corresponds to TP53R175H, one of the most frequent mutations in AML. Mice with somatic Trp53 mutation died due to lymphoma, however, Mdm2 haploinsufficient mice combined with Trp53 mutation succumbed to AML. The disease was immunophenotypically and histologically characterized as AML based on the bone marrow histopathology and expression of Cd11b and Ly6A on the surface of leukemic cells. Immunohistopathology of bone marrow and spleen of MdmLOH p53Mut showed a highly proliferative AML characterized by strong nuclear expression of Ki67 and mutant p53 in the bone marrow of mice. Together, our data identifies Mdm2 LOH to be essential for malignant transformation of p53 mutant myeloid lineage leading to AML development.
Andreeff:Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding; Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy; Amgen: Research Funding; Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees.
