Haploinsufficiency for Myc delays leukemia development. (A) Bone marrows of PML-RARA Myc^+/+ or PML-RARA Myc^+/− FVB/n mice were harvested and transplanted into lethally irradiated FVB/n recipient animals. Combined results from eight (Myc^+/+) or eleven (Myc^+/−) independent transplantation experiments are shown. Mice were followed for the development of leukemia. Nonleukemic deaths were censored at the time of death. 67% of PML-RARA Myc^+/+ deaths were from leukemia, whereas 31% of PML-RARA Myc^+/− recipient mice died of leukemia. Median latency among leukemic animals was 258 d for Myc^+/+ and 339 d for Myc^+/−. P < 0.0001. (B) Morphology of leukemias arising in PML-RARA Myc^+/− mice. Results representative of 16 leukemias are shown. (i) Cytology of leukemic cells from spleen of mouse #836. L, Lymphocyte. Histology of (ii) bone marrow of mouse #828, (iii) spleen of mouse #828, and (iv) liver of mouse #828. (i) Wright’s Giemsa stain. (ii-iv) H&E stain. Bars: (i) 8 µm; (ii) 12 µm; (iii and iv) 60 µm; (iii inset) 24 µm. (C) Gain of chromosome 15 and the wild-type Myc allele in PML-RARA Myc^+/− leukemias. The number of copies of chromosome 15 as determined by cytogenetic analysis is indicated for each sample; 2 previously characterized leukemias (#1111 and #1127), 5 PR+Myc^+/− leukemias, and 1 nonleukemic PR+Myc^+/− marrow. Copy numbers for the wild-type Myc and Pgk-hprt alleles are also given for the same samples. Samples were run in triplicate in one to eight independent experiments. Pgk-hprt copy number could not be determined for leukemia #5727 because of insufficient quantity of DNA. *, Pgk-hprt copy number values are 0. Results for leukemia #836 showing no gain of chromosome 15, but increased copy-number for the wild-type Myc allele, are not shown here, but are included in Table I and discussed in the text.