Genomic Disruption of CAMKMT by t(2;11)(p21;q23) Reveals a Glycolytic Reprogramming Mechanism in Acute Myeloid Leukemia.

INTRODUCTION The t(2;11)(p21;q23) translocation without KMT2A rearrangement has been reported in ~16 hematologic neoplasms, but its molecular target(s) remain unknown. We aimed to identify the genes disrupted by this translocation and to clarify its contribution to Acute Myeloid Leukemia (AML) pathogenesis.

Methods

We performed Whole-Genome Sequencing (WGS), targeted RNA next-generation sequencing (86-gene panel), and transcriptome profiling on diagnostic bone-marrow samples from a 64-year-old male with AML. Karyotype analysis and Sanger sequencing confirmed chromosomal breakpoints and fusion junctions. CAMKMT expression and correlations with glycolysis-related genes were validated in TCGA (n = 173) and GTEx (n = 70) datasets.

Results

Karyotyping revealed a main clone with sole t(2;11)(p21;q23) and a subclone with an additional del(5q). WGS uncovered an inverted, tail-to-tail fusion between CAMKMT (2p21) and GRIA4 (11q22.3) that truncates both genes. RNA-seq showed marked CAMKMT down-regulation (p < 0.01) and up-regulation of ENO1, PGK1, GPI, TPI1, and CXCL2 (all p < 0.05). Public datasets confirmed that low CAMKMT expression inversely correlates with these glycolytic genes (r = -0.18 to -0.31; p < 0.05). No functional chimeric protein is predicted.

Discussion

CAMKMT truncation, rather than a gain-of-function fusion, appears to drive leukemogenesis by reprogramming energy metabolism. This mechanism aligns with CAMKMT's role as a negative regulator of glycolysis and calmodulin signaling. However, a major limitation of the present study is the lack of protein-level evidence, which precludes definitive confirmation that functional loss of CAMKMT occurs at the cellular level.

Conclusion

We demonstrate that the t(2;11)(p21;q23) translocation is associated with disruption of CAMKMT at the genetic level and may promote leukemogenesis through metabolic reprogramming. These findings broaden the molecular spectrum of AML and suggest CAMKMT loss as a potential therapeutic vulnerability. However, our conclusions are based on transcriptomic evidence, and protein-level validation will be required in future studies to confirm the functional consequences of CAMKMT disruption.