RESUMO
The t(5;14)(q31.1;q32.1) associated with B-lymphoblastic leukemia/lymphoma (B-ALL/LBL) is a rare, recurrent genetic abnormality recognized as a distinct entity by the 2017 World Health Organization (WHO) classification. In these cases, the IGH enhancer region (14q32.1) is juxtaposed to the vicinity of the IL3 gene (5q31.1), resulting in increased production of interleukin-3 (IL3) and subsequently a characteristic reactive eosinophilia. B-ALL with t(5;14)(q31.1;q32.1) may have a low lymphoblast count that can complicate detection of t(5;14)(q31.1;q32.1) by conventional chromosome studies. We have identified four patients with IGH/IL3 rearrangements despite normal conventional chromosome studies in each case [one patient had a non-clonal t(5;14)(q31;q32) finding]. Fluorescence in situ hybridization utilizing a laboratory-developed IGH break-apart probe set identified IGH rearrangements in three of four cases, and a next generation sequencing (NGS) based assay, mate-pair sequencing (MPseq), was required to characterize the IGH/IL3 rearrangements in each case. Three patients demonstrated a balanced t(5;14)(q31.1;q32.1) while one patient had a cryptic insertion of the IL3 gene into the IGH region. These results demonstrate that NGS-based assays, such as MPseq, confer an advantage in the detection of IGH/IL3 rearrangements that are otherwise challenging to characterize by traditional cytogenetic methodologies.
Assuntos
Rearranjo Gênico/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Interleucina-3/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Biópsia por Agulha/métodos , Medula Óssea/patologia , Criança , Cromossomos Humanos Par 14 , Citogenética/métodos , Eosinofilia/imunologia , Feminino , Humanos , Hibridização in Situ Fluorescente/métodos , Cariótipo , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Translocação Genética , Adulto JovemRESUMO
T-lymphoblastic leukemia/lymphoma (T-ALL/LBL) accounts for approximately 15% of pediatric and 25% of adult ALL. While the underlying frequency of KMT2A (MLL) gene rearrangements has been identified in approximately 4-8% of T-ALL/LBL cases, a paucity of literature is available to characterize further the KMT2A rearrangements in pediatric/young adult T-ALL/LBL. A 10-year retrospective review was performed to identify KMT2A rearrangements in specimens sent for T-ALL/LBL fluorescence in situ hybridization studies in patients under the age of 30 years. Of 806 T-ALL/LBL FISH studies performed on unique individuals, 27 (3.3%) harbored KMT2A rearrangements. Nineteen patients were male and eight were female (M:F ratio, 2.4:1) with ages ranging from 1 to 20 years (mean 12, median 12). Of the 27 cases, nine (33%) had KMT2A/MLLT1 fusions, eight (30%) had KMT2A/AFDN fusions, two (7%) had KMT2A/ELL fusions, and one (4%) had a KMT2A/MLLT10 fusion. In addition, five (19%) had KMT2A rearrangements with unidentified gene fusion partners and two (7%) had 3'KMT2A deletions. Our results indicate that MLLT1 and AFDN account for the majority (63%) of KMT2A gene partners in pediatric/young adult T-ALL/LBL, while no KMT2A/AFF1 or KMT2A/MLLT3 fusions were observed despite their common identification in B-ALL and acute myeloid leukemia, respectively. In addition to diagnostic and prognostic value, detecting specific KMT2A fusions may also be of clinical importance in the era of targeted therapies.