Mechanisms of mixed-lineage leukemia

Abstract

Advances in our understanding of the genetic determinants of leukemia have translated to better treatment options and improved survival of patients with acute myeloid and acute lymphoid leukemia. However, some leukemias, such as those bearing 11q23 (MLL) translocations, result in aggressive diseases with a relatively poor prognosis, despite improved treatments such as allogeneic hematopoietic stem cell transplantation. This article will briefly review the functions and regulation of wild-type MLL during normal hematopoiesis, while focusing on recent advances in our understanding of the molecular mechanisms governing MLL leukemias. The transcriptional targets, cooperating signaling pathways and molecular machinery involved in MLL-associated leukemias will be discussed, as well as how these may be harnessed for more personalized treatment of this disease.

Figure 1. Normal and mutated forms of the mixed-lineage leukemia protein

(A) The wild-type MLL protein is shown schematically with conserved domains indicated and labeled. MLL is cleaved into two fragments, MLL^N and MLL^C. The site of taspase-mediated protein cleavage is indicated. AT-hooks and the CxxC domain of MLL^N bind to DNA, while the plant homeodomain/bromo region aids in localization and protein regulation. A SET and TAD domain contributes to histone methylation and recruitment of histone acetyltransferases. BCR is the site of fusion in the event of chromosomal translocations. MLL fusion proteins contain a sequence of a fusion partner protein fused in-frame to the MLL^N fragment at the BCR. MLL-PTDs duplicate the MLL sequence from the AT-hooks through the CxxC domain that is inserted at the BCR. Proteins are not drawn to scale. (B) HSC differentiation to a monocyte is shown, including intermediate progenitor cells: MPPs, CMPs and GMPs. MLL fusion proteins are capable of transforming HSCs through GMPs into LSCs that gives rise to leukemia. BCR: Breakpoint cluster region; CMP: Common myeloid progenitor; GMP: Granulocyte/monocyte progenitor; HSC: Hematopoietic stem cell; LSC: Leukemic stem cells; MLL: Mixed-lineage leukemia; MLL-PTD: MLL partial tandem duplications; MPP: Multipotent progenitor.

Figure 2. Targeting mixed-lineage leukemia fusion protein complexes and cooperating pathways

A representative MLL fusion protein complex is shown that recruits a transcriptional activation complex. Varieties of this complex have been termed EAP [122], SEC [59] and AEP [58]. Included in the recruitment are p-TEFb and the histone H3K79 methyltransferase DOT1l. Menin and PAFc bind directly to MLL fusion proteins, aiding in target recognition. BRD4 associates with PAFc and is required for MLL fusion protein function. GSK3 is shown associated with Axin and APC, which are involved in several signaling pathways including the WNT/β-catenin pathway. FLT3 activates several signaling pathways, including the Ras pathway that cooperates with MLL fusion proteins leading to leukemia. Compounds known to inhibit some of these processes and protein interactions are shown. ac: Acetylation; me: Methylation; MLL: Mixed-lineage leukemia; PAFc: PAF complex.