Identification of new translocations involving ETV6 in hematologic malignancies by fluorescence in situ hybridization and spectral karyotyping

Abstract

TEL/ETV6 is the first transcription factor identified that is specifically required for hematopoiesis within the bone marrow. This gene has been found to have multiple fusion partners; 35 different chromosome bands have been involved in ETV6 translocations, of which 13 have been cloned. To identify additional ETV6 partner genes and to characterize the chromosomal abnormalities more fully, we studied bone marrow samples from patients known to have rearrangements of 12p, using fluorescence in situ hybridization (FISH) and spectral karyotyping (SKY). FISH analysis was done with 14 probes located on 12p12.1 to 12p13.3. Nine ETV6 rearrangements were identified using FISH. The aberrations include t(1;12)(p36;p13), t(4;12)(q12;p13) (two patients), t(4;12)(q22;p13), t(6;12)(p21;p13), der(6)t(6;21)(q15;q?)t(12;21)(p13;q22), t(6;12)(q25;p13), inv(12)(p13q24), and t(2;2;5;12;17)(p25;q23;q31;p13;q12). Six new ETV6 partner bands were identified: 1p36, 4q22, 6p21, 6q25, 12q24, and 17q12. Our present data as well as previous data from us and from other researchers suggest that ETV6 is involved in 41 translocations. The breakpoints in ETV6 were upstream from the exons coding for the HLH (helix-loop-helix) domain in six cases. Although cytogenetic analysis identified 12p abnormalities in all cases, FISH and SKY detected new and unexpected chromosomal rearrangements in many of them. Thus, complete characterization of the samples was achieved by using all three techniques in combination.

Disruption of ETV6 in intron 2 results in upregulatory and insertional events in childhood acute lymphoblastic leukaemia

“…[3][4][5][6][7][8][9] There is some evidence that the gene is more often involved when the 12p rearrangements are balanced rather than unbalanced, the latter often being associated with a complex karyotype. 10,11 The inherent instability of the ETV6 gene has been demonstrated in several different studies by the use of cosmid probes to its individual exons. However, the series of probes used have not always covered the complete gene, so the significance of some findings is unclear.…”

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

“…2). Our SKY analyses of 11 of the 19 cases have been reported [3,23]. The clinical features and the karyotype of the remaining 8 cases are given in Table 2.…”

“…Giemsa-banded karyotypes were described according to International System for Human Cytogenetic Nomenclature (ISCN 1995) [16]. FISH analysis was performed using 12 cosmid and 3 phage probes located on 12p12.1 to 12p13.3, as previously described [3]. ETV6/TEL was analyzed by 5 cosmids that cover the gene, and KIP1/CDKNIB using two P1 phage clones [17,18].…”

“…The ETV6 gene (formerly called TEL ), a member of the ETS family of transcription factors, is the most common target for rearrangements in 12p13 [1,2]. Since its initial description, ETV6 has been found rearranged with more than 40 chromosome bands [3]. To date, 17 partner genes have been identified and cloned; however, several other genes mapping to 12p13 could also be relevant in leukemogenesis, including CDKN1B/KIP1 , an important negative regulator of the cell cycle.…”

NUP98 is fused to HOXA9 in a variant complex t(7;11;13;17) in a patient with AML-M2

“…The clones were labeled with Spectrum Green, Spectrum Orange (Vysis), or DEAC (NEL 455; Perkin-Elmer Life Sciences Inc, Boston, MA), by nick translation. FISH analysis was performed on BM metaphases as previously described [20]. Samples were obtained from the patient with informed consent.…”