Characterization of Pediatric Acute Myeloid Leukemia With t(7;12)(q36;p13)

Acute myeloid leukemia (AML) with t(7;12)(q36;p13) is a recurrent translocation in AML in infants or very young children and was recently included in the World Health Organization (WHO) Classification of Hematolymphoid Tumors. AML with t(7;12) is reported to involve MNX1 and ETV6 signaling; however, the mechanism of leukemogenesis is not well understood, and the presence of MNX1::ETV6 fusion transcripts has only been confirmed in approximately 50% of cases. In contrast, high expression of MNX1 has been seen in all investigated cases. In this study, we investigated the clinical as well as biological characteristics of 12 pediatric AML with t(7;12) and performed whole transcriptome (WTS) and whole genome sequencing (WGS) on six of these. There was no significant difference in event-free survival or overall survival of these t(7;12) AML patients compared with other AML in the same age group. Interestingly, WTS identified several fusion transcripts involving ETV6 but not together with MNX1. WGS identified the genomic breakpoints and revealed that a common fusion partner on chromosome 7 was NOM1. Principal component analysis (PCA) of the WTS data showed that all t(7;12) AML cases cluster together, separate from all other pediatric AML subtypes; all cases had high expression of MNX1, MNX1-AS1, and MNX1-AS2. Hence, t(7;12) AML, despite expressing different fusion transcripts and with varying translocation breakpoints, constitutes a phenotypically homogenous subgroup. This underlines that the leukemia-driving event most likely is ectopic expression of MNX1 and that this therefore should be the defining Classifying criteria of this type of AML.