Cryptic Rearrangement of the KMT2A Gene in a B-cell Acute Lymphoblastic Leukemia

A 30-year-old female diagnosed with B cell acute lymphoblastic leukemia (B-ALL) had a normal karyotype at diagnosis.

The case was investigated further by fluorescence in situ hybridization (FISH), array comparative genomic hybridization (aCGH), and reverse-transcription polymerase chain reaction (RT-PCR) followed by Cycle sequencing. The diagnostic karyotype was normal (46,XX), but FISH studies on tumor cells using a KMT2A break-apart probes showed that the proximal part of KMT2A was inserted into an apparently normal chromosome 4 with concomitant loss of the distal part of the probe. aCGH identified losses within 11q23.3 and 4q21.3q22.1 with the breakpoints mapping inside the KMT2A and AFF1 loci. The presence of the putative KMT2A::AFF1 fusion gene was confirmed by FISH analysis and RT-PCR/Cycle sequencing; an in-frame fusion was detected between KMT2A (exon 9) and AFF1 (exon 6). The patient underwent allogenic stem cell transplantation and reached complete remission.

This case highlights the need to supplement banding cytogenetics with appropriate molecular (cyto)genetic techniques whenever the karyotype does not reveal characteristic aberrations. Although KMT2A rearrangements in both lymphoblastic and myeloid acute leukemias usually arise through karyotypically visible chromosomal recombinations, this is not always the case.