Open AccessSomatic cancer mutations in the MLL 1 histone methyltransferase modulate its enzymatic activity and dependence on the WDR 5/ RBBP 5/ ASH 2L complex
Author(s) -
Weirich Sara,
Kudithipudi Srikanth,
Jeltsch Albert
Publication year - 2017
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12041
Subject(s) - biology , mutant , methyltransferase , histone methyltransferase , genetics , mutation , methylation , gene
Somatic missense mutations in the mixed lineage leukemia 1 ( MLL 1) histone H3K4 methyltransferase are often observed in cancers. MLL 1 forms a complex with WDR 5, RBBP 5, and ASH 2L ( WRA ) which stimulates its activity. The MM ‐102 compound prevents the interaction between MLL 1 and WDR 5 and functions as an MLL 1 inhibitor. We have studied the effects of four cancer mutations in the catalytic SET domain of MLL 1 on the enzymatic activity of MLL 1 and MLL 1– WRA complexes. In addition, we studied the interaction of the MLL 1 mutants with the WRA proteins and inhibition of MLL 1– WRA complexes by MM ‐102. All four investigated mutations had strong effects on the activity of MLL 1. R3903H was inactive and S3865F showed reduced activity both alone and in complex with WRA , but its activity was stimulated by the WRA complex. By contrast, R3864C and R3841W were both more active than wild‐type MLL 1, but still less active than the wild‐type MLL 1– WRA complex. Both mutants were not stimulated by complex formation with WRA , although no differences in the interaction with the complex proteins were observed. These results indicate that both mutants are in an active conformation even in the absence of the WRA complex and their normal control of activity by the WRA complex is altered. In agreement with this observation, the activity of R3864C and R3841W was not reduced by addition of the MM ‐102 inhibitor. We show that different cancer mutations in MLL 1 lead to a loss or increase in activity, illustrating the complex and tumor‐specific role of MLL 1 in carcinogenesis. Our data exemplify that biochemical investigations of somatic tumor mutations are required to decipher their pathological role. Moreover, our data indicate that MM ‐102 may not be used as an MLL 1 inhibitor if the R3864C and R3841W mutations are present. More generally, the efficacy of any enzyme inhibitor must be experimentally confirmed for mutant enzymes before an application can be considered.