CYTOGENETIC ANALYSIS OF CD34(+) SUBPOPULATIONS IN AML AND MDS CHARACTERIZED BY THE EXPRESSION OF CD38 AND CD117

It has been supposed in de novo AML that malignant transformation occu rs at the level of committed progenitors. Recent data of our group and others provide evidence that in AML malignant transformation may regu larly occur at the level of stem cells. These cells can be discriminat ed by function and specific surface molecules. CD34, a glycophosphopro tein, is a cellular surface antigen characteristically expressed by st em cells. CD34(+) stem cells can be further subdivided by the expressi on of additional surface molecules like CD38 and CD117. In this articl e we present results from cytogenetic examinations of FACS-isolated st em cell subpopulations in eight patients (four AML and four MDS). Six of them displayed clonal karyotype abnormalities at the time of first diagnoses in the native bone marrow (5q-; 5q- and complex abnormalitie s; +8; inv(16) and +8; i(17q) and -21; i(21q)). We used CD117, the rec eptor for the stem cell factor (also KIT oncogene) as a new cellular s urface marker. CD34(+)/CD117(+/-) stem cell subpopulations were examin ed in two patients with AML and three patients with MDS. We found leuk emic stem cells in every type of stem cell subpopulation examined (CD3 4(+)/CD38(-), CD34(+)/CD38(+), GD34(+)/CD117(-) CD34(+)/CD117(+)). Sec ondary, progression-associated chromosome abnormalities likewise were demonstrable in GD34(+) cells. In three patients a mosaic of normal an d abnormal metaphases was found in the highly purified stem cell subpo pulations. We conclude that in AML and MDS stem cells are the target o f leukemogenic genetic defects. CD117 as a new marker to isolate diffe rent CD34(+) subpopulations was not sufficient to discriminate between normal and leukemic stem cells. Our findings have implications for au tologous stem cell transplantation, high-dose chemotherapy and the pat hogenetic concept of leukemogenesis.