PIG-A, DAF and proto-oncogene expression in paroxysmal nocturnal haemoglobinuria-associated acute myelogenous leukaemia blasts.
Failed surface expression of the complement decay-accelerating factor (DAF) due to mutation of the PIG-A gene is a hallmark of affected paroxysmal nocturnal haemoglobinuria (PNH) blood elements. Previous findings that acute myelogenous leukaemia (AML) blasts evolving in a PNH patient differed from idiopathic AML blasts in that they exhibited DAF negativity suggested that the leukaemic blasts derived from an affected PNH cell. To investigate whether these cells differ from untransformed PNH cells in PIG-A genetic alterations or in DAF mRNA processing, or are distinguishable from conventional AML blasts in proto-oncogene activation or chromosomal structure, their DNA and RNA were examined using PIG-A, DAF and proto-oncogene probes and their karyotype was analysed. Analyses of the PIG-A genome revealed dual exchanges of A1110-->G and T1130-->A resulting in conversions of T370 to R and I377 to N in the coding region but no deletions or rearrangements. Investigations of DAF mRNA processing showed mRNA species differing in 3' UT regions from those in untransformed cells but similar to those in DAF-positive leukaemia cell lines. Studies of c-myb, c-myc, c-fos and c-fms showed no gross genetic alterations, amplifications or variations in mRNA transcripts deriving from these genes. Karyotypic analysis showed no alterations. The results indicate that in AML blasts evolving in PNH: (1) the PIG-A genome exhibits multiple point mutations but no gross genetic changes; (2) DAF mRNA transcripts exhibit differentiation-dependent variations that do not affect GPI-anchoring; (3) c-myb, c-myc, c-fos and c-fms activation show no differences from idiopathic AML; and (4) no karyotypic abnormalities are associated with AML transformation.
Stafford, HA; Nagarajan, S; Weinberg, JB; Medof, ME
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