Exploring tumour suppressor ATRX and telomere maintenance in MLLr leukaemia

Thesis

The acquisition of limitless replicative potential, is crucial for cancer development. Normally, cells undergo senescence once the telomeres (sequences that protect genes from being lost after replication due to the end replication problem), reach a critically short length. In cancer, two mechanisms are known to maintain telomere length: the upregulation of the enzyme Telomerase and the Alternative Lengthening of Telomeres (ALT) pathway. The ALT pathway has defining features of increased long non-coding telomeric repeat containing RNA (TERRA), extrachromosomal DNA (C-circles), ALT associated PML bodies (APBs), heterogeneous telomere lengths and the loss of the tumour suppressor protein ATRX.

Mixed Lineage Leukaemia-1 (MLL-1) is a histone methyltransferase required for histone 3 lysine 4 trimethylation (H3K4me3) during normal development. The MLL gene is mutated in 70-90% of infant leukaemia and is associated with a poor clinical outcome. The most common MLL gene mutations in leukaemia are gene rearrangements (MLLr). Especially translocations that fuse MLL in-frame with common partners such as AF4, AF9 or ENL, creating novel MLL fusion proteins (MLL-FP). Although ALT is relatively rare in leukaemias, recent evidence of MLL-1 binding to telomeric repeats, coupled with it driving TERRA transcription raises interesting questions as to how telomeres are regulated in MLL fusion driven leukaemias.

Here, we show that telomeric sequences are bound by MLL-1 in MLL-AF4 cell lines. We also show an increase of the telomere transcript, TERRA and other hallmarks of ALT, such as reduction of ATRX and presence of C-circles in cell lines that have the MLL translocation.

Understanding the role of ATRX and telomere maintenance may provide new insight into how these therapy resistant MLLr leukaemias are initiated or maintained.

Authors: Gracias, D

• DOI: 10.5287/ora-zogqqzkjq
• Type of award: MSc by Research
• Level of award: Masters
• Awarding institution: University of Oxford