Characterization of a recurrent translocation t(2;3)(p15–22;q26) occurring in acute myeloid leukaemia

Abstract

Six patients with de novo acute myeloid leukemia (AML) and a t(2;3)(p15-21;q26-27) were identified among approximately 1000 cases enrolled in the GIMEMA trial. The t(2;3) was the sole anomaly in three patients, whereas in three cases monosomy 7, trisomy 15 and 22, and trisomy 14 represented additional aberrations. No cryptic chromosome deletions at 5q, 7q, 12p, and 20q were observed. One patient carried a FLT3 D835 mutation; FLT3 internal tandem duplication (ITD) was not detected in three patients tested. Characterization of the translocation breakpoints using a 3q26 BAC contig specific for the PRDM3 locus showed that the breakpoints were located 5 0 to EVI1 as follows: within myelodysplatic syndrome (MDS) intron 1 (# 3), between MDS1 exons 2 and 3 in three patients (# 1, 2, 4) with a 170 bp cryptic deletion distal to the breakpoint in one (# 2), and in a more centromeric position spanning from intron 2 to the 5 0 region of EVI1 (# 6, 5). A set of 2p16-21 BAC probes showed that the breakpoints on chromosome 2p were located within BCL11A in two separate regions (# 1, 4 and # 2-5), within the thyroid adenoma-associated (THADA) gene (# 6) or distal to the ZFP36L2 locus (# 3). Regulatory elements were present in proximity of these breakpoints. RACE PCR studies revealed a chimeric transcript in 1/6 patient analyzed, but no fusion protein. Quantitative PCR showed a 21-58-fold overexpression of the EVI1 gene in all cases analyzed. The patients showed dysplasia of at least two myeloid cell lineages in all cases; they had a low-to-normal platelet count and displayed an immature CD34 þ CD117 þ immunophenotype. Despite intensive chemotherapy and a median age of 43 years (range 36-59), only two patients attained a short-lived response; one patient is alive with active disease at 12 months, five died at 4-14 months. We arrived at the following conclusions: (a) the t(2;3) is a recurrent translocation having an approximate 0.5% incidence in adult AML; (b) breakpoints involve the 5 0 region of EVI1 at 3q26, and the BCL11A, the THADA gene or other regions at 2p16.1-21; (c) cryptic deletions distal to the 3q26 breakpoint may occur in some cases; (d) the juxtaposition of the 5 0 region of EVI1 with regulatory elements normally located on chromosome 2 brings about EVI1 overexpression; (e) clinical outcome in these cases is severe.

A Rare Case of Acute Myeloid Leukemia with a t(2;3) Chromosomal Translocation Characterized by Thrombophilia and Chemoresistance

“…However, breakpoint analyses of the short arm of chromosome 2 have failed to identify a common pathobiological mechanism as of yet. 3,5 Our report reinforces the notion made by previous reports, that AML with t(2;3)(p21;q26) including the EVI1 locus is associated with symptomatic thrombophilia, chemoresistance and adverse risk. 4 On a clinical level, we conclude that the occurrence of AML with t(2;3)(p21;q26) warrants up-front treatment intensification as induction chemotherapy alone failed to induce complete remission.…”

“…Indeed, t(3;3) and inv(3) were found to rearrange an oncogenic distal GATA2 enhancer on 3q21 resulting in ectopic EVI1 activation and concomitant GATA2 haploinsufficiency. 7 Accordingly, in AML with t(2;3), ectopic expression of EVI1 was observed in most cases, 3,5 albeit involvement of the oncogenic GATA2 enhancer seems unlikely to contribute to EVI1 overexpression in this entity as assessed by breakpoint analyses of 3q26. However, breakpoint analyses of the short arm of chromosome 2 have failed to identify a common pathobiological mechanism as of yet.…”

“…The morphological assessment of the peripheral blood revealed 25% myeloblasts (Fig. 1A) Carsten-Oliver Schulz, 1) Philipp Hemmati, 5) Renate Arnold, 5) Hanno Riess, 1,5) and Philipp le Coutre 1,5) We hereby report a case of acute myeloid leukemia with translocation t(2;3) and involvement of the ectopic virus integration site-1 (EVI1) gene. Like most other 3q26-related disorders reported thus far, we describe a phenotype with elevated platelet counts and dysmegakaryopoesis.…”

“…To our knowledge, there are only 17 cases of AML with t(2;3) reported to this date (Table 1), [3][4][5] which resemble some properties of inv(3) and t(3;3) AML. This case report should expand our understanding of biology, risk and prognosis of AML with t(2;3).…”

t(2;3)(p16;q26) BCL11A/MECOM

“…Four cases to date; there were three male and one female patients; patients were aged 36, 36, 36, and 55 (in years) (Trubia et al, 2006).…”