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IER3 (formerly IEX-1) encodes a 27-kDa glycoprotein that regulates death receptor-induced apoptosis, interacts with NF-kappaB pathways, and increases expression rapidly in response to cellular stresses such as irradiation. Animal models, gene expression microarray experiments, and functional studies in cell lines have suggested a potential role for IER3 in oncogenesis, but, to date, no abnormalities of IER3 at the DNA level have been reported in patients with neoplasia. Here, we describe breakpoint cloning of a t(6;9)(p21;q34) translocation from a patient with a myelodysplastic syndrome (MDS), facilitated by conversion technology and array-based comparative genomic hybridization, which revealed a rearrangement translocating the IER3 coding region away from critical flanking/regulatory elements and to a transcript-poor chromosomal region, markedly decreasing expression. Using split-signal and locus-specific fluorescence in situ hybridization (FISH) probes, we analyzed 204 patients with diverse hematological malignancies accompanied by clonal chromosome 6p21 abnormalities, and found 8 additional patients with MDS with IER3 rearrangements (translocations or amplification). Although FISH studies on 157 additional samples from patients with MDS and a normal-karyotype were unrevealing, and sequencing the IER3 coding and proximal promoter regions of 74 MDS patients disclosed no point mutations, reverse transcription-PCR results suggested that dysregulated expression of IER3 is common in MDS (61% >4-fold increase or decrease in expression with decreased expression primarily in early MDS and increased expression primarily in later MDS progressing toward leukemia), consistent with findings in previous microarray experiments. These data support involvement of IER3 in the pathobiology of MDS.

To better estimate prognosis for patients with myelodysplastic syndromes (MDS) associated with clonal interstitial deletions of the long arm of chromosome 5 (del(5q)), we reviewed the medical records of 130 adults with del(5q) MDS seen at our institution over a 15-year period. Overall median survival of this cohort was 9.5 months, shorter than reported in earlier series. The least favorable outcomes are associated with complex cytogenetics, lack of any normal metaphases, normocytic rather than macrocytic erythrocyte indices, and low baseline lymphocyte counts. Lymphopenia but not neutropenia at the time of diagnosis appears to be a new adverse prognostic indicator. Cytogenetic breakpoints defined by G-banded karyotyping correlate poorly with particular disease features. Surprisingly, survival of patients with treatment-related MDS was equivalent to that of de novo MDS with del(5q) in this series. Morphologic features associated with del(5q) are diverse. Most patients with del(5q) MDS do not meet criteria for WHO-defined 5q-syndrome, and the presence of del(5q) does not appear to modify the clinical phenotype otherwise risk-stratified by the International Prognostic Scoring System (IPSS). Additional important prognostic factors not taken into account by the IPSS include the baseline erythrocyte indices, lymphocyte count, and clonal burden., (Copyright 2008 Wiley-Liss, Inc.)

The purpose of this study was to define the spectrum of hematologic neoplasms and chromosomal breakpoints associated with del(5q); separate analyses were performed to account for prior cytotoxic treatment. A total of 358 consecutive del(5q) cases were identified; specific diagnoses included myelodysplastic syndrome (MDS; 53%), acute myeloid leukemia (AML; 22%), plasma cell proliferative disorder (PCPD; 9%), myeloproliferative disorder (MPD; 7%), acute lymphoblastic leukemia (ALL; 2%), PCPD with MDS (2%), MDS/MPD (2%), and malignant lymphoma (ML; 2%). The corresponding figures in the absence/presence of prior cytotoxic treatment (n=250/108) were 61%/34% for MDS, 24%/19% for AML, 4%/20% for PCPD, 6%/8% for MPD, 1%/4% for ALL, and 2%/4% for ML. del(5q) occurred as the sole cytogenetic abnormality in 88 cases (25%) including 76 without prior cytotoxic therapy. Among the latter, 82% had MDS, 8% AML, 5% MPD, 4% PCPD, and 1% ML. Chromosome 5 breakpoints included q13q33 in 49% of the cases, q15q33 in 22%, q22q33 in 8%, and q13 in 3% and their distribution was not affected by specific diagnosis or treatment history. del(5q)-associated lymphoid disorders featured a higher prevalence of previous cytotoxic therapy and smaller number del(5q)-positive metaphases, when compared to their counterparts with myeloid neoplasms. We conclude that del(5q), although most prevalent in MDS, is seen across the spectrum of myeloid disorders including MPD and its occurrence in lymphoid disorders might signify, for the most part, an occult myeloid clone.