Concomitant aberrant overexpression of RUNX1 and NCAM in regenerating bone marrow of myeloid leukemia of Down's syndrome.

BACKGROUND AND OBJECTIVES Myeloid leukemia of Down's syndrome (ML-DS) has characteristic biological features (e.g. expression of the truncated GATA1s), which are different from those of non-DS childhood acute myeloid leukemias (AML). The objective of this study was to investigate factors predisposing to the development of ML-DS. DESIGN AND METHODS We analyzed 134 bone marrow specimens from 64 children with ML-DS and non-DS AML during chemotherapy and 7 specimens from DS children with- out leukemia,who did not receive any chemotherapy,The specimens were analyzed by multiparameter flow cytometry and quantitative reverse transcriptase polymerase chain reaction for transcription factors involved in hematopoiesis. RESULTS Samples taken from children with ML-DS in complete remission during chemotherapy aberrantly expressed CD56 (NCAM) at the surface of monocytic and granulocytic cells. Compared to non-DS AML cases,children with ML-DS had a statistically significant higher proportion of CD56+ cells in the CD33+ fraction: 71%+/-6% vs. 4%+/-1% (p<0.00001). A significant decrease of the amount of CD33+/CD56+ cells was observed during and after maintenance therapy. An increased number of CD33+/CD56+ cells was also present (>85%) in children with DS who did not receive chemotherapy, but showed a left-shift (due to infection), compared with DS children without left-shift (<10% CD33+/CD56+ cells). Within the CD33+/CD56+ fraction, RUNX1 was overexpressed more than 5-fold (p<0.02) compared to CD33+/CD56- cells, whereas there were no differences regarding GATA1, SPI1, ERG or ETS-2 levels. INTERPRETATION AND CONCLUSIONS The combined overexpression of RUNX1 and NCAM during stress hematopoiesis in children with DS might be a key factor in the development of overt leukemia and/or in the growth advantage of the malignant GATA1s clone in ML- DS.