LEDGF: a leukemia-specific target

The goal of precision medicine is to be able to specifically target the disease state in individual patients with minimal toxic side effects. A detailed understanding of the molecular basis of a disease is an important aspect of achieving this goal. Part of this is understanding the context-dependent activity of specific targets, the most important comparison being normal cells vs the disease state. It is challenging to answer these questions precisely in humans; thus, animal models provide a robust system for answering clearly defined questions about context specific function.

LEDGF (also known as PC4 and SFRS1-interacting protein 1 or PSIP1) was originally identified as the p75/p52 component of PC4, a transcriptional coactivator.²  It is also famous for being the integration target of HIV.³  Importantly, LEDGF also has a crucial role in the development of a rare but aggressive subset of leukemias caused by mutations in the mixed lineage leukemia (MLL) gene.⁴  The most common MLL mutations fuse MLL in frame with a wide range of different partner genes creating novel fusion proteins (MLL-FPs).⁵  MLL-FPs cause leukemia by binding to gene targets and causing their inappropriate upregulation. LEDGF was originally proposed to be crucial for anchoring MLL-FP proteins to their specific gene targets,⁴  but more recent work has suggested that LEDGF may instead have a different role in controlling the assembly of other transcription components at gene targets.⁶ 

Because LEDGF has a clear importance in leukemia progression, several attempts have been made to inhibit the LEDGF/MLL-FP interaction.^4,7,-9  One key piece of information that has been missing until now is whether a robust inhibitor would disrupt normal blood development. In other words, is there a therapeutic window where one could effectively target LEDGF without causing more general toxic effects in the blood system?

Using a hematopoietic-specific knockout system, El Ashkar et al completely removed LEDGF from normal blood cells in the mouse. They found that, although there were some measurable defects in hematopoiesis, overall the mice were healthy and still retained a fully functional hematopoietic system. Conversely, cells that were deleted for LEDGF were completely resistant to developing MLL-FP–driven leukemia, although other oncogenes were still able to transform these cells.¹  Together, these data suggest that it is now worth developing more robust inhibitors to LEDGF because it appears to be possible to disrupt MLL-FP leukemogenesis without affecting normal blood cell development.

Although this work focuses on a specific target protein that is only important in a rare subset of leukemias, it represents an important proof of principle. This study provides an important example of the robust information needed to justify a more comprehensive drug development program. It also highlights that there may be very few general targets that will work across multiple different cancers. If this is the case, individual patients may themselves represent their own rare kind of cancer, potentially requiring similar specific information on an increasingly wide range of different candidate therapeutic targets.