Aberrant expression of p21RAS but not p120GAP is a common feature of myelodysplasia.
The RAS gene family encodes signal transducing proteins which are involved in the regulation of cell growth and differentiation. Constitutively 'activating' point mutations of RAS have been detected at high frequency in preleukaemia and acute leukaemia, however, the distribution of expression of p21RAS in normal or preleukaemic primary haematopoietic cells has not been studied. We have examined the expression of p21RAS and its negative regulator/downstream effector, p120GAP, in combination with lineage-specific cluster of differentiation markers in normal and preleukaemic myeloid bone marrow cells using flow cytometry. Normal bone marrow was characterized by low and uniform levels of p21RAS expression throughout all lineages analysed. In contrast, 28% (9/32) of patients with myelodysplastic syndrome (MDS) over-expressed p21RAS. In three of these patients a single over-expressing peak of p21RAS expression was observed, with no evidence of a population exhibiting expression within the normal range. In 6/32 MDS patients over-expression of p21RAS was observed only in a subpopulation of the myeloid cells. Follow-up samples were analysed in three of these six patients; over-expression was confirmed in each patient and in two patients a relative expansion of the over-expressing cell population was observed. Eight out of nine of the patients with aberrant p21RAS expression were diagnosed with low-risk MDS. From 21 MDS patients screened for p120GAP expression, no reduction or loss of expression was observed, however, one AML patient demonstrated a heterogeneous pattern of expression. p120GAP expression was lower (P < 0.05) in the AML group than in normals. The results of the study suggest that over-expression of the RAS gene product, p21RAS, may represent an alternative or additional mechanism of activation of the RAS signalling pathway and that this may play a role in leukaemogenesis, however, there is no evidence from this study that loss of p120GAP expression is a feature of myelodysplasia.
D000293:Adolescent; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000378:metabolism; D015153:Blotting, Western; D001853:Bone Marrow / Q000378:metabolism; D005434:Flow Cytometry; D020690:GTPase-Activating Proteins; D006801:Humans; D016130:Immunophenotyping; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000378:metabolism* / Q000473:pathology; D011506:Proteins / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D020703:ras GTPase-Activating Proteins
D015703:Antigens, CD; D020690:GTPase-Activating Proteins; D011506:Proteins; D020703:ras GTPase-Activating Proteins; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)