Infant acute leukemia with lineage switch at relapse expressing a novel t(4;11)(q21;q23) MLL-AF4 fusion transcript

Abstract

Background. A high occurrence of translocation t(4;11)(q21;q23) was reported in infant acute lymphoblastic leukemia (ALL) leading to the fusion of the mixed lineage leukemia (MLL) gene on chromosome 11 and the AF4 gene on chromosome 4. More than 50 distinct MLL-AF4 types of fusion have been previously identified, none of those reported matching the peculiarities found in an infant ALL case to be reported below. Materials and methods. Molecular tests were performed for the detection of TEL-AML1, BCR-ABL(p190), E2A-PBX1, and MLL-AF4 in the peripheral blood sample of a 21 days newborn boy suspected of ALL. An unexpected MLL-AF4 fragment was identified, further purified, and later analyzed by sequencing. Flow cytometry analyses were carried out at diagnosis and relapse on a FACSCanto-II cytometer (Becton-Dickinson). Results. The patient was found to be positive for the MLL-AF4 transcript, with an uncommonly long-sized product and a previously undescribed sequence (in-frame fusion between exon 12 of MLL and exon 4 of the AF4 gene). The immunophenotypic analyses also showed a particular development: while at diagnosis a dominant malignant clone displaying a B lymphoid precursor phenotype was described, at relapse a malignant monocytoid population predominantly expanded. The presence of MLL-AF4 e12-e4 transcript was still manifest at relapse, without other transcript characteristic for myeloid lineage. Conclusions. To our knowledge, this is the first report of a MLL-AF4 rearrangement revealing this complex transcript with new breakpoints in MLL. Its early detection may predict an immunophenotypic switch and may assist the clinicians in designing optimized therapies.

Epigenetic regulator genes direct lineage switching in MLL-AF4 leukaemia

“…Lineage switch acute leukaemias (LSALs) lose their lymphoid specific features and gain myeloid phenotype upon relapse (Jiang et al, 2005;Germano et al, 2006;Park et al, 2011;Carulli et al, 2012;Rossi et al, 2012;Ivanov et al, 2013). Alternatively, MLL-AF4 leukaemias may harbour distinct lymphoid and myeloid populations at the same time, thus classifying as mixed phenotype acute leukaemias (MPALs) of the bilineage subtype.…”

The impact of immunological and biomolecular investigations on the outcome of children with acute lymphoblastic leukemia - experience of IIIrd Paediatric Clinic Timisoara

“…There are several methods used for MRD assessment: immunophenotyping using flow cytometry, PCR analysis of fusion products resulting from chromosomal translocations, and RQ-PCR to determine the remission status. (8)(9)(10)(11) …”