The DCC Heterozygote Reduces the Latency Period and Changes the Disease Phenotype of Myeloproliferative Disease in p230BCR/ABL-Expressing Mice.

Chronic neutrophilic leukemia (CNL) is a distinct disease form with less aggressive phenotype mimicking chronic myelogenous leukemia (CML). CNL sometimes has a unique p230BCR/ABL gene abnormality, as does Philadelphia-positive myeloproliferative disease (MPD) mimicking essential thrombocythemia (Ph+ET). The reason of the phenotypic difference between CNL and Ph+ET remains unclear. Recently, we have generated the p230BCR/ABL-transgenic mice, whose disease phenotype is MPD mimicking ET, to study the disease phenotype. In studies of human leukemia cells, loss of DCC (deleted colorectal carcinoma) gene expression is reported in about 20% of CML cases.

To investigate whether loss of DCC expression plays a role in the disease phenotype of p230BCR/ABL-expressing MPD, we crossmated p230BCR/ABL-transgenic (BCR/ABL^Tg/−) mice with DCC-heterogenous (DCC^+/−) mice, thereby generating p230BCR/ABL-transgenic, DCC-heterogenous (BCR/ABL^Tg/− DCC^+/−) mice.

BCR/ABL^Tg/− DCC^+/− mice have a short latency (9 to 12 months) compared with BCR/ABL^Tg/− DCC^+/+ mice (17 to 20 months) for developing overt MPD. Less thrombocytosis (91–140x10⁴/mm³) was found in the BCR/ABL^Tg/− DCC^+/− transgenic littermates compared with the BCR/ABL^Tg/− DCC^+/+ transgenic littermates (115–170 x 10⁴/mm³). Leukocytosis and the percentage of granulocytes in BCR/ABL^Tg/− DCC^+/− mice were greatly increased compared with BCR/ABL^Tg/− DCC^+/+ transgenic littermates (6.1–13.5 x 10³/mm³ vs 5.0–11.2 x 10³/mm^3; 42–68 % vs 23–49 %). However, blasts, which were detected in the blastic crisis, were not found in the peripheral blood of either mouse line.

Thus, the DCC-heterozygote, in cooperation with p230BCR/ABL cDNA, shortened the latency period of overt MPD, and changed the disease phenotype from MPD mimicking ET to MPD mimicking CNL. However, pathological analysis of the bone marrow, spleen, liver, etc. did not reveal any difference between the BCR/ABL^Tg/− DCC^+/− transgenic littermates and the BCR/ABL^Tg/− DCC^+/+ transgenic littermates.