Autosomal dominant erythrocytosis and pulmonary arterial hypertension associated with an activating HIF2 alpha mutation.

reaction (PCR) methods as previously described in detail.1,2 Forty-six (1.8%) cases showed an ambiguous result and were not considered for further analysis. Of the remaining 2498 cases, 904 (36.2%) were BCR-ABL (599 24% minor breakpoint region [m-bcr] and 282 11.3% major breakpoint region [M-bcr], 15 0.6% both, M-bcr and m-bcr, and 8 atypical transcripts), and 1594 were BCR-ABL . Atypical transcripts were not systematically detected before 20001 and thus had to be excluded from further analysis. We grouped patients into age cohorts at 10-year intervals according to their age at diagnosis, each comprising between 277 and 481 patients and found a remarkable increase of BCR-ABL frequency in adolescents and young adults (Figure 1). It increased from 12.7% in adolescents (15-24 years) to 30.6% and 43.7% in patients aged 25 to 34 and 35 to 44 years, respectively. In patients older than 44 years, the BCR-ABL frequency showed no further increment and ranged between 42% and 44%. The increase of BCRABL frequency was paralleled by a relative increase of M-bcr transcripts. These transcripts accounted for 16.4% of all BCR-ABL-positive cases in adolescents (15-24 years). Their relative frequency increased to 22.5% in 25to 34-year-olds and to 36.8% in 35to 44-year-olds and remained between 33% and 36.2% from then on. The reason for this age dependency is not obvious. The relative frequencies of immunologic subtypes (78.2% common, 19.9% pre-B, 1.9% pro-B) of BCR-ABL patients did not differ significantly across the age groups. Moreover, the frequency of BCR-ABL was also not significantly different in woman compared with men. Our study excluded lymphatic blast crises in patients with known chronic myeloid leukemia (CML). Previous work has indicated that M-bcr– and m-bcr– positive ALL may arise from different sets of hematopoietic progenitor cells,3 but this does not explain the age dependency.Anumber of genetic markers in ALL show a marked age dependency (reviewed in Armstrong and Look4), eg, TEL-AML1, TLX1, and TLX3, MLL aberrations (especially in infant ALL). Our data provide additional information on the biology of BCR-ABL-positive ALL and substantiate evidence of age-dependent variation in the genetic background of ALL.