Acute leukemias harboring KMT2A/MLLT10 fusion: a 10‐year experience from a single genomics laboratory

Abstract

The MLLT10 (formerly AF10) gene is the fourth most common KMT2A fusion partner across all acute leukemias and requires at least 3 breaks to form an in‐frame KMT2A/MLLT10 fusion due to the opposite orientation of each gene. A 10‐year retrospective review was performed to identify individuals from all age groups that harbor KMT2A/MLLT10 fusion obtained by our KMT2A/MLLT10 dual‐color dual‐fusion fluorescence in situ hybridization (D‐FISH) assay. Of the 60 unique individuals identified, 31 were male and 29 were female (M:F ratio, 1.1:1) with ages ranging from 3 days to 86 years (mean 21.5 years, median 5.5 years). The diagnoses included acute myeloid leukemia (AML) (49 patients, 82%), B‐ or T‐lymphoblastic leukemia/lymphoma (7 patients, 12%), myeloid sarcoma (3 patients, 5%), and a single case (2%) of undifferentiated leukemia. Twenty‐seven of 49 patients (55%) with AML were in the infant or pediatric age group. Fifty‐three of 60 patients (88%) had KMT2A/MLLT10 D‐FISH signal patterns mostly consisting of single fusions. In addition, 10 (26%) of 38 patients with conventional chromosome studies had “normal” (5 patients) or abnormal (5 patients) chromosome studies that lacked structural or numeric abnormalities involving chromosomes 10 or 11, implying cryptic cytogenetic mechanisms for KMT2A/MLLT10 fusion. Lastly, mate‐pair sequencing was performed on 4 AML cases, 2 of which had “normal” chromosome studies and cryptic KMT2A/MLLT10 fusion as detected by KMT2A/MLLT10 D‐FISH studies, and verified the multiple breaks required to generate KMT2A/MLLT10 fusion.

Cytogenetics of Pediatric Acute Myeloid Leukemia: A Review of the Current Knowledge

“…Thus, in order to create a functional chimeric KMT2A - MLLT10 , a simple reciprocal translocation between chromosomes 10 and 11 is not sufficient, and other mechanisms, such as inversion or insertion, are necessary to correctly orientate the gene segments. Thus, accurate FISH analysis, using a break-apart probe covering KMT2A and/or a fusion probe covering both genes, is recommended alongside PCR analyses for accurate diagnosis of this poor prognosis rearrangement [ 92 ]. Moreover, t(10;11)(p12;q23)/ KMT2A-MLLT10 can closely resemble t(10;11)(p12;q14)/ PICALM/MLLT10 , a rare abnormality currently assigned to an intermediate risk group [ 54 ].…”

<p>miR-331-3p Inhibits Tumor Cell Proliferation, Metastasis, Invasion by Targeting MLLT10 in Non-Small Cell Lung Cancer</p>

“…19 Based on previous studies, MLLT10 gene has been reported as a crucial fusion partner gene in specific leukemic fusions; one of its frequent fusion genes is mixed-lineage leukemia (MLL, also known as KMT2A) detected in acute leukemias, with the translocation t(10;11)(p13;q23). 20,21 Another common fusion gene is phosphatidylinositol-binding clathrin assembly lymphoid-myeloid (PICALM, previously called as CALM), with the translocation t(10;11)(p13;q21). 22 In addition, NAP1L1-MLLT10 recombination was found in pediatric T-acute lymphoblastic leukemia.…”

Identification of predictive genetic signatures of Cytarabine responsiveness using a 3D acute myeloid leukaemia model

“…Table shows the 14 gene fusions and the samples that they occur. Eight out of the 14 gene fusions have been previously reported, leaving 6 novel ones. To confirm these novel gene fusions, the gene fusion supporting reads were aligned to the fusion sequences to check the break points ().…”