RARITY OF DOMINANT-NEGATIVE MUTATIONS OF THE G-CSF RECEPTOR IN PATIENTS WITH BLAST CRISIS OF CHRONIC MYELOID-LEUKEMIA OR DE-NOVO ACUTE-LEUKEMIA

It is likely that leukemia results, at least in part, from mutations t hat lead to a block in the normal process of differentiation. A define d region of the cytoplasmic domain of the granulocyte colony-stimulati ng factor receptor (G-CSF-R) transmits signals for maturation or diffe rentiation of myeloid progenitor cells. Mutations in this region have been found in some patients with severe congenital neutropenia (SCN) w ho subsequently evolved to acute myeloid leukemia (AML). To determine if mutations of the G-CSF-R are more widespread in hematological malig nancies, we have investigated a total of 47 patients, including 29 pat ients with blast crisis of chronic myeloid leukemia (CML-BC) and 18 pa tients with de novo acute leukemia as well as 19 normal controls, by R T-PCR and SSCP analysis. Two point mutations were found in a single in dividual with secondary AML (FAB type Mi). The first was heterozygous and is predicted to replace the normal glutamine at position 718 with a stop codon, leading to a truncated protein. An identical mutation ha s been described previously and shown to act in a dominant negative ma nner. The second mutation was homozygous and would substitute a lysine for the normal glutamic acid at position 785. No mutations were found in any other patient or control samples. We conclude that mutations i n the cytoplasmic domain of the G-CSF-R are infrequent in CML-BC or ac ute leukemia but may contribute to malignant transformation in some ca ses.