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

Area of Science:

• Hematology
• Oncology
• Genetics

Background:

• A 30-year-old female diagnosed with B cell acute lymphoblastic leukemia (B-ALL) presented with a normal karyotype.
• This normal karyotype obscured underlying genetic abnormalities crucial for diagnosis and treatment.

Purpose of the Study:

• To investigate the genetic basis of B-ALL in a patient with a normal karyotype.
• To identify cryptic chromosomal rearrangements, specifically KMT2A alterations, using advanced molecular techniques.

Main Methods:

• Fluorescence in situ hybridization (FISH) with KMT2A break-apart probes.
• Array comparative genomic hybridization (aCGH) to detect copy number variations and breakpoints.
• Reverse-transcription polymerase chain reaction (RT-PCR) followed by sequencing to confirm gene fusions.

Main Results:

• FISH revealed a KMT2A rearrangement involving insertion into chromosome 4.
• aCGH identified breakpoints within the KMT2A and AFF1 loci.
• RT-PCR and sequencing confirmed an in-frame KMT2A::AFF1 fusion gene (exon 9 of KMT2A fused with exon 6 of AFF1).

Conclusions:

• This case underscores the importance of molecular cytogenetic techniques in diagnosing B-ALL when conventional karyotyping is unrevealing.
• KMT2A rearrangements, a known driver in acute leukemias, can occur without visible chromosomal aberrations on standard karyotyping.
• Early identification of such cryptic rearrangements is vital for appropriate patient management and therapeutic strategies.