MUTATIONS OF THE GRANULOCYTE-COLONY-STIMULATING FACTOR-RECEPTOR IN PATIENTS WITH SEVERE CONGENITAL NEUTROPENIA ARE NOT REQUIRED FOR TRANSFORMATION TO ACUTE MYELOID-LEUKEMIA AND MAY BE A BYSTANDER PHENOMENON

Point mutations of the granulocyte-colony stimulating factor receptor (G-CSFR) resulting in an abnormally truncated receptor have been impli cated in the pathogenesis of some cases of severe congenital neutropen ia (SCN) and in the transformation of SCN to acute myeloid leukaemia ( AML), We report here studies in 11 patients with SCN. No mutations wer e detected in the one patient who developed AML indicating that develo pment of such mutations is not a prerequisite for transformation. Trun cation mutations were detected in a minor percentage of transcripts fr om two other patients. In one patient the mutation has been constant a t a low level (5-10% of total mRNA and 2/40 myeloid colonies) for 2 ye ars. In the other patient the mutation was acquired, remained present at low levels for nearly 3 years and then spontaneously disappeared. B oth patients had polyclonal haemopoiesis. We hypothesize that these mu tations do not cause SCN, are randomly acquired with the mutant clone being expanded to detectable le-cds by high levels of exogenous or end ogenous G-CSF, and may disappear by clonal succession. In a pre-leukae mic marrow the mutated subclone could achieve high levels, but this do es not necessarily indicate a primary role of the mutant receptor in t he leukaemogenic process.