ANALYSIS OF THE CODING SEQUENCE FOR THE GM-CSF RECEPTOR-ALPHA AND BETA-CHAINS IN PATIENTS WITH JUVENILE CHRONIC MYELOID-LEUKEMIA (JCML)

Peripheral blood granulocyte-macrophage progenitors (CFU-GMs) from pat ients with juvenile chronic myeloid leukemia (JCML) are able to prolif erate spontaneously in the absence of exogenous growth factors and stu dies have shown that these progenitors display a hypersensitive growth response to GM-colony-stimulating factors (CSFs) in culture. We scree ned RNA from six patients with JCML for mutations in the GM-CSF recept or (GM-CSFR) coding sequence using RT-PCR-SSCP. Altered patterns were found in five patients for the GM-CSFR a chain, and in five patients f or the beta chain. Two nucleotide substitutions accounted for all alph a chain abnormalities; one was conservative for Val(333) and the other caused an Ala(17) --> Gly substitution. Both had previously been dete cted in normal controls. Sequencing of beta chain abnormalities reveal ed four base substitutions. Three were previously described polymorphi sms, one causing a Pro(603) --> Thr substitution and two conservative point mutations involving Ser(426) and Pro(648). A further nucleotide mutation, which resulted in a Glu(249) --> Gln substitution, was also found but is not thought to be of pathological significance. Polymorph isms of the GM-CSFR or and beta chains are common, but pathogenic poin t mutations of the GM-CSFR are infrequent in patients with JCML and ar e unlikely to be involved in the hypersensitivity to GM-CSF demonstrat ed by progenitor cells.