LOC100289656 is overexpressed in both subgroups of MLL-rearranged AML.

  • Major finding:LOC100289656 is overexpressed in both subgroups of MLL-rearranged AML.

  • Approach: Next-generation sequencing highlighted fusion events and oncogenic mutations in MLL-rearranged AML.

  • Impact: Cotreatment with MEK and RTK inhibitors may benefit MLL-rearranged patients with RAS pathway mutations.

Rearrangements involving the gene encoding the histone H3 lysine 4 methyltransferase MLL (also known as KMT2A) occur via translocation or partial tandem duplication (PTD) and are observed in 10% to 15% of acute myeloid leukemias (AML). Despite shared aberrations in the MLL gene, expression profiles from MLL-fusion (MLL-F) and MLL-PTD AMLs display little overlap in gene expression, suggesting distinct molecular origins. Recent work, however, indicates that both subtypes exhibit similar sensitivity to inhibitors of DOT1L, a histone methyltransferase that interacts with MLL-fusion genes. To more closely examine the relationship between MLL-F and MLL-PTD AMLs, Lavallée and colleagues performed next-generation sequencing of 415 samples, including 31 MLL-F and 23 MLL-PTD samples. Comparison of transcriptional profiles revealed 140 discriminative genes, of which 84 were overexpressed, including the HOXA–HOXB gene cluster, and 56 were underexpressed in MLL-F AMLs. Surprisingly, the majority of these genes (80%) have not been previously characterized in MLL-F, including adjacent genes and pseudogenes LOC100289656, GOLGA6L7P, WHAMMP2, PDCD6IPP2, and GOLGA8M located on chromosome 15q13.1. In line with these results, exogenous expression of an MLL fusion gene upregulated LOC100289656 expression in vivo. Subsequent analysis of AML samples with increased LOC100289656 expression also identified MLL-PTD leukemias, suggesting a common genetic marker in MLL-rearranged AML, and highlighted previously undetected MLL fusion events with MLLT10 or ENAH. Within the MLL-F cohort, recurrent missense mutations were detected in the SPI1 transcription factor gene, and 45% of samples were characterized by mutations in RAS pathway genes, which conferred heightened sensitivity to MEK inhibitors and decreased sensitivity to receptor tyrosine kinase (RTK) inhibitors. Combined treatment with MEK and RTK inhibitors synergistically inhibited the growth of RAS-mutant MLL-F cells. Together, these data highlight how integration of transcriptome and chemical sensitivity profiles can be instrumental in molecularly characterizing disease subtypes and provide a rationale for combining MEK and RTK inhibitors in patients with MLL-F AML harboring RAS pathway mutations.

Lavallée VP, Baccelli I, Krosl J, Wilhelm B, Barabé F, Gendron P, et al. The transcriptomic landscape and directed chemical interrogation of MLL-rearranged acute myeloid leukemias. Nat Genet 2015 Aug 3 [Epub ahead of print].