Characterization of 12p molecular events outside ETV6 in complex karyotypes of acute myeloid malignancies

Abstract

Summary. Acute myeloid disorders with rearrangements of 12p outside the ETV6 gene were characterized bȳ uorescence in situ hybridization (FISH) with a panel of DNA probes. Seven patients with de novo acute myeloid leukaemia (AML), one with secondary acute myeloid leukaemia (sAML), and one in the blast phase of chronic myeloid leukaemia (CML-BP) were enrolled in the study. All AML cases showed multiple karyotypic changes. Chromosome 5 and/or 7 deletions were the most frequent accompanying changes. FISH revealed ampli®cation, cryptic translocation, and fragmentation of chromosome 12, not discernible at karyotypic level. Different karyotypic rearrangements of 12p showed a common molecular event. Among the seven cases in which breakpoints could be determined, six were telomeric and one centromeric to ETV6. In three AML cases a new recurrent breakpoint in the telomeric region was identi®ed distally to locus D12S158 and to pac 922B22 which is the most telomeric probe available for 12p. Accompanying cryptic deletions were also detected in ®ve patients and the commonly deleted region, of around 700 kb, included the ETV6 gene and the D12S391 locus.

Molecular cytogenetic characterization of breakpoints in 19 patients with hematologic malignancies and 12p unbalanced translocations

“…Cases with unbalanced 12p translocations appear to be closely associated with complex karyotypes, and in most cases the breakpoints have been reported to be outside ETV6, as was true for all our patients [14,15]. SKY is an important tool to characterize the aberrations in these cases [23].…”

“…The probes used in the hybridization are shown on the left. breakpoint in the subtelomeric region of 12p [14]. The localization of the most telomeric probe used by La Starza et al [14] is between 12p13.32 and 12p13.33 (D12S158), the same region as our probe (D12S235).…”

“…These deletions in some cases are different from the region reported in ETV6-CBFA2 positive ALL [12]. Unbalanced translocations involving ETV6 have rarely been described [13,14], and cases with breakpoints outside ETV6 appear to be strongly associated with complex karyotypes [14,15].…”

ETV6 mutations and loss in AML-M0

“…Most abnormalities consist of total or partial loss of 12p usually affecting ETV6 and CDKN1B, implicating these genes as tumor-suppressor genes. [1][2][3][4] Recently, heterozygous mutations of ETV6, resulting in loss of repressor activity, were found in AML, adding to the view that ETV6 might have tumor-suppressor characteristics. 5 Whereas translocations and deletions involving ETV6 have been reported in AML-M0, ETV6 mutations were never investigated specifically in this subtype.…”

Breakpoint analysis by fluorescence in situ hybridization in myelodysplastic syndromes with t(3;12)(q26;p13) and expression of EVI1

“…7-9 ETV6 appears to be involved in different translocations associated with myelodysplasia (MDS) and acute leukemia, sometimes resulting in chimaeric transcripts. 4,10,11 In t(12;22)(p13;q11) the MN1-ETV6 fusion protein may be involved in transformation of myeloid progenitor cells while the CBFA2-ETV6 transcript as a result of t(12;21)(p13;q22) may play a role in malignant transformation of lymphoid cells. A fusion of ETV6 with PDGFRB (platelet-derived growth factor receptor ␤-gene) in t(5;12) or fusion to a tyrosine kinase domain of ABL in t(9;12)(q34;p13) may alter tyrosine kinase activity of PDGFRB and ABL, respectively, affecting both lymphoid and myeloid lineages.…”