Quantitative comparison of the expression of EVI1 and its presumptive antagonist, MDS1/EVI1, in patients with myeloid leukemia

Abstract

The EVI1 gene in chromosome band 3q26 exhibits a number of properties consistent with a role as an oncogene, and its expression is activated in most myeloid leukemia patients with, as well as in a minority of patients without, 3q26 rearrangements. A splice variant of this gene, MDS1/EVI1, acts as its antagonist at least in some tissue culture assays. We established real-time quantitative reverse transcriptase polymerase chain reaction (RTQ-RT-PCR) assays for these mRNA variants to compare their expression levels in a quantitatively reliable manner. EVI1 was overexpressed to highly variable extents in all patients with, as well as in 14% of patients without, 3q26 rearrangements. In some of these samples, MDS1/EVI1 was also transcribed at elevated levels compared to those of healthy controls. However, although the induction of MDS1/EVI1 was comparable to, or higher than, that of EVI1 in three of five samples with a normal EVI1 locus, this was true for only two of 13 patients with a 3q26 aberration. We further provide preliminary evidence that the RTQ-RT-PCR assay may be useful for disease monitoring in patients overexpressing EVI1.

Molecular characterization of a t(1;3)(p36;q21) in a patient with MDS. MEL1 is widely expressed in normal tissues, including bone marrow, and it is not overexpressed in the t(1;3) cells

“…However, our experiments showed a strong expression of MEL1 and cMEL in the heart, lung, kidney and pancreas, which should have been easily detected by Mochizuki et al (Figure 3b). Interestingly, a recent report showed the same profile expression in the analysis of MDS1/EVI1 (PR positive) versus cEVI1, a region common to MDS1/ EVI1 and EVI1 (PR negative type), using a similar experimental design (Vinatzer et al, 2003). The expression of both genes was stronger in the same tissues, with the only exception of placenta, where MDS1-EVI1 and cEVI1 are highly expressed, whereas MEL1 and cMEL are poorly expressed.…”

“…However, a review of the literature shows that not all members of the PRdomain family work in the same way. Two recent studies detected in 17/21 (81%) patients with t(3;3) or inv(3) that high EVI1 expression was associated with high MDS1-EVI1 expression, the form with the PR domain (Barjesteh van Waalwijk van Doorn- Khosrovani et al, 2003;Vinatzer et al, 2003). Moreover, lack of expression of the PR-lacking form EVI1 has been reported in several cases with syndrome 3q21q26 (Fichelson et al, 1992;Morishita et al, 1992;Soderholm et al, 1997;Langabeer et al, 2001), suggesting that the molecular mechanism of leukemogenesis is not the same in all patients.…”

A potential role for PRDM12 in the pathogenesis of chronic myeloid leukaemia with derivative chromosome 9 deletion

“…5 Studies of RIZ, MDS-EVI1, MEL1 and BLIMP-1 have revealed that a variety of tumour types often overexpress the PR domain-negative product, relative to the fulllength protein. 4,5,7,9 It is tempting to speculate that in our patient, the distal insertion breakpoint abrogated sequences coding for the 5 0 PR domain of PRDM1, thus causing a relative decrease in the proportion of PR-domain-positive product.…”

“…3 In addition, structural rearrangement, mutation and/or aberrant expression of RIZ, MDS-EVI1 and MEL1 have been reported in myeloid malignancies. 4,7,9 PRDM family members share the feature of expressing two protein products that differ in the presence or absence of the PR domain. 5 Studies of RIZ, MDS-EVI1, MEL1 and BLIMP-1 have revealed that a variety of tumour types often overexpress the PR domain-negative product, relative to the fulllength protein.…”

“…Several groups, including our laboratory, have investigated this marker on CLL B cells and found that greater than 30% CD38 expression within a CLL leukemic population correlates to an overall shorter time to progression and, in general, a poor clinical outcome. [1][2][3][4][5] However, another study suggests that scoring CLL B-cell CD38 expression using both percent-positive and mean fluorescence intensity (MFI) is a more accurate prognostic tool for B-CLL patients. 6 Recently, Ghia et al 7 found that even a small distinct population of CD38 pos cells, displayed as a small peak in a bimodal CD38-staining profile, was associated with progressive disease.…”