Clonality analysis using X-chromosome inactivation at the human androgen receptor gene (HUMARA) - Evaluation of large cohorts of patients with chronic myeloproliferative diseases, secondary neutrophilia, and reactive thrombocytosis

Chronic myeloproliferative diseases (MPDs) are not associated with consiste nt cytogenetic or molecular abnormalities. Demonstration of clonal cell gro wth by analysis of X-chromosome inactivation (XCI) patterns in females prov ides a promising tool for diagnosis. However; this technique can be complic ated by excessive lyonization of normal cells mimicking clonal cell growth. We analyzed XCI patterns at the human androgen receptor (HUMARA) leaks in 146 healthy females, 65 women with secondary neutrophilin, 31 women with re active thrombocytosis, and 86 women with chronic MPDs. A skewed XCI pattern with greater than 75% amplification of 1 allele (allele ratio >3:1) was fo und in 22 (9.1%) of 242 control subjects. The incidence of skewing was stat istically significantly lower in women younger than 30 years (2/73) compare d with women older than 60 years (10/53). Of 86 patients with a chronic MPD , 71 (82%) exhibited an allele ratio greater than 3:1, whereas only 10 (12% ) of 86 age-matched control subjects showed a skewed XCI pattern. Although statistical evaluation of the delta showed a significant difference between patients with a chronic MPD and control subjects, proof of clonality in in dividual, especially elderly, patients is difficult.