ACQUIRED SKEWING OF X-CHROMOSOME INACTIVATION PATTERNS IN MYELOID CELLS OF THE ELDERLY SUGGESTS STOCHASTIC CLONAL LOSS WITH AGE

More frequent skewing of X-chromosome inactivation patterns (XCIPs) oc curs in the white blood cells of elderly females; this study was perfo rmed to determine whether this occurs in myeloid or lymphoid lineages. XCIPs were analysed in purified neutrophils and T cells from 80 femal es > 75 years and the results were compared with 23 cord blood and 94 younger adult blood samples. The degree of XCIP skewing in cord blood and younger adult blood cells was similar, with 3-4% having >90% expre ssion of one allele. Skewing was markedly increased in the neutrophils of elderly females, with 33% having >90% expression of one allele (P < 0.0001). Extreme skewing was present in only 9% of the elderly T-cel l samples and no evidence of T-cell clonality was found by PCR analysi s of the TCR gamma gene. The high level of acquired skewing of the XCI Ps in myeloid cells of the elderly suggests that with time there is a change in stem cell usage with stochastic loss of some of the original stem cells. This has ma)or implications for the use of XCIP analysis in the diagnosis of myeloid malignancies in the elderly and for gene t herapy into haemopoietic stem cells.