How to effectively treat acute leukemia patients bearing MLL-rearrangements ?

Biochem Pharmacol. 2018 Jan;147:183-190. doi: 10.1016/j.bcp.2017.09.007. Epub 2017 Sep 21.

Abstract

Chromosomal translocations - leading to the expression of fusion genes - are well-studied genetic abberrations associated with the development of leukemias. Most of them represent altered transcription factors that affect transcription or epigenetics, while others - like BCR-ABL - are enhancing signaling. BCR-ABL has become the prototype for rational drug design, and drugs like Imatinib and subsequently improved drugs have a great impact on cancer treatments. By contrast, MLL-translocations in acute leukemia patients are hard to treat, display a high relapse rate and the overall survival rate is still very poor. Therefore, new treatment modalities are urgently needed. Based on the molecular insights of the most frequent MLL rearrangements, BET-, DOT1L-, SET- and MEN1/LEDGF-inhibitors have been developed and first clinical studies were initiated. Not all results of these studies have are yet available, however, a first paper reports a failure in the DOT1L-inhibitor study although it was the most promising drug based on literature data. One possible explanation is that all of the above mentioned drugs also target the cognate wildtype proteins. Here, we want to strengthen the fact that efforts should be made to develop drugs or strategies to selectively inhibit only the fusion proteins. Some examples will be given that follow exactly this guideline, and proof-of-concept experiments have already demonstrated their feasibility and effectiveness. Some of the mentioned approaches were using drugs that are already on the market, indicating that there are existing opportunities for the future which should be implemented in future therapy strategies.

Publication types

  • Review

MeSH terms

  • Acute Disease
  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Gene Rearrangement*
  • Histone Deacetylase Inhibitors / pharmacology
  • Histone Deacetylase Inhibitors / therapeutic use*
  • Histone-Lysine N-Methyltransferase / genetics*
  • Histone-Lysine N-Methyltransferase / metabolism
  • Humans
  • Leukemia / drug therapy*
  • Leukemia / genetics*
  • Leukemia / metabolism
  • Myeloid-Lymphoid Leukemia Protein / genetics*
  • Myeloid-Lymphoid Leukemia Protein / metabolism
  • Treatment Outcome

Substances

  • Antineoplastic Agents
  • Histone Deacetylase Inhibitors
  • KMT2A protein, human
  • Myeloid-Lymphoid Leukemia Protein
  • Histone-Lysine N-Methyltransferase