A Lack of Correlation between EVI1 Expression, MDS Subtype and Karyotype Abnormalities Suggests Multiple Pathways Involved in EVI1 Impact on Hematopoietic Cells in MDS Patients.

EVI1 proto-oncogene located on human chromosome 3q26 has been repeatedly described as an important gene involved in pathogenesis of human acute myeloid leukemia or myelodysplastic syndrome (MDS). EVI1 encodes a nuclear DNA binding protein and its abnormal expression in immature hematopoietic cells leads to altered proliferation and differentiation of both erythroid and myeloid lineages. In our study, an incidence and prognostic relevance of EVI1 expression was studied in a group of 62 patients with different subtypes of primary MDS. EVI1 expression was detected using semiquantitative RT-PCR on samples obtained repeatedly from bone marrow and peripheral blood of patients or healthy controls. The results for individual cDNAs corresponding to the amounts of individual EVI1 mRNAs were related to the amount of standard housekeeping constitutively expressed GAPDH (glyceraldehyde 3-phosphate dehydrogenase). Abnormal EVI-1 expression was found in 12 out of 62 patients (19%). The distribution of positive patients according to the WHO classification was: RA-2, RCMD-3, 5q- syndrome-1, RAEB I.-3, RAEB II.-1, sAML -2, that represented 0% (RARS,CMML), 17% (RCMD,RAEB II.), 18% (sAML), 30%(RA,5q-syndrome) and 33% (RAEB I.) of all patients studied. Only 2 out of 12 patients with abnormal EVI-1 expression had abnormalities of chromosome 3. confirmed by mFISH, 2 patients had complex karyotype abnormalities involving chromosome 11. Five out of 50 negative patients had complex abnormalities including loss of chromosome 3. in 1 patient and abnormities of chromosome 11. in 2 patients. No significant difference in median survival and rate of leukemic transformation was observed between both the groups (25,0 months and 33% in EVI1 positive group vs. 15,3 months and 28% in EVI1 negative group, P=0,35). Nevertheless, in four EVI1 negative patients with RCMD or RAEB I. an abnormal EVI1 expression occurred repeatedly at the time of progression to RAEB I.or RAEB II. All these patients subsequently died on refractory AML. Our results suggest that abnormal EVI1 expression may play role in early MDS (eg. by impairment of erythropoiesis due to blocking of GATA-1 dependent transcription) as well as in advanced MDS (eg. by stimulation of proliferation and alteration of differentiation of myeloid precursors by inhibition of TGF_β or IFN_α signalling pathway). This may be an explanation for limited prognostic relevance of abnormal EVI1 expression in MDS patients in our study. However, a novel occurrence of EVI1 expression in the course of the disease might serve as an additional adverse prognostic factor.