BCL11B

And this suggested to us that there probably was a relationship between these alterations in copy number state and the deregulation of the gene.

And using additional approaches, such as looking at chromosome looping and gene acetylation, which is a mark of enhancers, K27 acetylation, we could show that this was the case, that these breaks here adjacent to NKX21 were then rearranged to a very strong enhancer at another locus called BCL11B, resulting in deregulation of the gene.

Now there are other loci where we know the gene is deregulated and we have not been able to find the nature of the rearrangement using this type of sequencing and this has pushed us into another phase of the project where we're using long read sequencing to more fully understand the nature of these rearrangements.

The second point I wanted to make is that we've been able to add more detail to some of the known targets of alteration in TLL.

The first is that the drivers of some of these subtypes, such as rearrangements of this gene, activation of this gene, define groups of leukemia that often transcend immunophenotype because they incorporate not just MPALs but other lineage-assigned cases, such as BALLs or indeed TALLs and AMLs for this gene.

The second is that they often result in therapeutic vulnerabilities, which we've shown are very active in preclinical models.

So for example, these cases that have activation of a gene called BCL11B have high levels of FLT3 and BCL2 expression.

And xenograft models of these leukemias are exquisitely sensitive to combined treatment with these two approved agents.