The genetics of MLL leukemogenesis

In the November 1st issue of G&D, Dr. Michael Cleary (Stanford University School of Medicine) and colleagues identify the gene Meis1 as a critical player in the establishment of leukemia stem cells, and the development of MLL leukemia.

Mixed lineage leukemia (MLL) is a distinctive type of leukemia – distinguished from the more prevalent acute lymphoblastic leukemia (ALL) by the presence of a break and rearrangement of chromosome number 11. The design of effective therapies to combat MLL leukemia depends upon the understanding of the unique genetic signature that underlies this disease.

This chromosomal translocation that characterizes MLL activates the histone methyltranferase enzyme called MLL, inducing it to turn-on downstream gene targets that transform blood progenitor cells into leukemia stem cells (LSCs).

While some of the downstream targets of MLL are known (Hox genes, for example), the genetic changes that are sufficient to drive MLL leukomogeneis have remained elusive. Dr. Cleary and colleagues focused their work on another group of proteins that are mis-expressed in MLL leukemias: the TALE (three-amino-acid loop extension) class of proteins.

The researchers found that one gene in particular – called Meis1 – is required for leukemia stem cell maintenance. In fact, the researchers showed that Meis1 regulates many important biological properties of the disease including differentiation arrest, cycling activity, in vivo progression and self-renewal of LSCs.

Dr. Cleary is confident that “The critical role of Meis1 and other TALE class proteins in MLL leukemia stem cells provides a promising avenue for future studies to design more selective therapies for this poor prognosis subtype of leukemia.”