Cryptic insertion and translocation or nondividing leukemic cells disclosed by FISH analysis in infant acute leukemia with discrepant molecular and cytogenetic findings

Abstract

Of 51 infants with acute leukemia, 13 (25%) had contradictory findings on 11q23/MLL rearrangements that were analyzed by cytogenetic and Southern blot methods: seven had rearranged MLL and normal karyotype, four had rearranged MLL and abnormal karyotype with no 11q23 translocation, and two had germline MLL and 11q23 translocations. Fluorescent in situ hybridization (FISH) analysis using an MLL probe that was performed to elucidate the discrepancy disclosed the presence of normal dividing cells and nondividing leukemic cells in the same bone marrow in five patients, and cryptic insertion or translocation in another five. Subsequent FISH and reverse transcription-polymerase chain reaction analysis identified the MLL-AF10, MLL-AF4, or MLL-AF1q fusions that were produced by the cryptic rearrangements in four of the five patients. In the remaining three patients, the breakpoint of 11q23 translocation was located distal to the MLL locus in one, and the discrepancy was unresolved in two. Thus, FISH should complement cytogenetic analysis when cytogenetic and molecular genetic findings are contradictory in infant leukemia, and when infant leukemia does not show 11q23 translocations or other specific translocations including t(7;12), t(1;22), etc that are recurrently found in infant leukemia.

Characterization of fusion partner genes in 114 patients with de novo acute myeloid leukemia and MLL rearrangement

“…The MLL/t11q23 group consisted of 12 partner genes: with 5 subtypes of MLL-AF9, MLL-AF10, MLL-ELL, MLL-AF6 and MLL-ENL accounting for 94%, of the remaining seven different MLL fusion transcripts, one subtype occurring in one patient. As demonstrated in the present series and also by others, 18,23,24 even 11q23 abnormalities were detected, the precise identification of MLL translocation partners was usually difficult.…”

“…[21][22][23] Moreover, previous studied have shown that a substantial proportion of cases with MLL rearrangements detected by molecular analysis were missed by standard cytogenetic studies or FISH. 15,16,18,[21][22][23][24] This was especially true in patients who had cytogenetically silent MLL-PTD. 15,16 Furthermore, 11q23 translocations were frequently but not invariably associated with MLL rearrangement.…”

Translocation t(11;19)(q23;q13.1) without <b><i>MLL </i></b>Rearrangement in Acute Myeloid Leukemia: Heterogeneity of the 11q23 Breakpoints

“…In line with a previously reported case of therapy-related pre-B ALL of unknown karyotype, they found that MLL/ACTN4 rearrangements appear to be therapy-related events. However, due to the rare occurrence of hematological malignancies involving t(11;19)(q23;q13), their clinical and genetic features have still to be fully characterized [2,3,4,5,6,7,8]. Here, we describe a new case of AML involving t(11;19)(q23;q13).…”

“…In addition to 2 cases reported by Yang et al [8], 5 other cases of hematological malignancies with t(11;19)(q23;q13) have been described in the literature (table 1) [3,4,5,6,7,8]; 3 revealed t(11;19)(q23;q13) as the sole abnormality, while age, sex, diagnosis, additional cytogenetic abnormalities and MLL status varied. However, apart from a case of T-cell lymphoma, acute leukemias and MDS with t(11;19)(q23;q13) seem to be classified into 3 groups (table 1): (1) therapy-related AML/ALL/MDS (Nos.…”

“…Of these, the t(11;19)(q23;q13) translocation is a very rare but recurrent aberration observed in acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) and myelodysplastic syndromes (MDS): only 6 cases have ever been reported [2,3,4,5,6,7,8]. Recently, Yang et al [8] demonstrated that MLL was fused to ACTN4 , encoding an ubiquitously expressed actin-bundling protein at 19q13 by t(11;19)(q23;q13.1) in therapy-related MDS.…”