Acute promyelocytic leukaemia (APL) is characterized by the accumulation of promyelocytes, although no one knows for certain why this particular stage of haematopoiesis is affected. Andrew Lane and Timothy Ley report in Cell that promyelocytes express high levels of a protease that facilitates leukaemogenesis.

Over 90% of patients with APL possess the t(15;17) translocation that leads to expression of the PML-RARα fusion protein. To investigate the function of this protein, Lane and Ley transiently expressed the fusion protein it in various myeloid and non-myeloid cell types, and observed that it was rapidly cleaved only in a promyelocytic cell line. Further analysis of the cell-specific proteolysis revealed that PML-RARα is cleaved by neutrophil elastase (NE), which is encoded by the ELA2 gene. ELA2 transcription is activated in early myeloid development, and maximally expressed at the early promyelocyte stage. The authors showed that human APL cells express ELA2, and that both mouse and human forms of NE are able to cleave both forms of PML-RARα.

But is this protease important for leukaemogenesis? When mice were engineered that transgenically expressed Pml-Rarα in promyelocytes, they all developed APL within 350 days. When this fusion protein was expressed in promyelocytes of mice of a NE-null background, however, only 45% of mice developed APL within the same time period. So, NE is important for the ability of Pml-Rarα to initiate APL. The effect is also specific for NE-null mice, as Pml-Rarα expression in mice that were deficient for the serine protease cathepsin G did not affect APL penetrance.

Several lines of evidence have indicated that PML-RARα requires an interaction with a factor that is present in early myeloid cells to initiate disease, so NE could be the long-sought-after APL cofactor. The authors propose that PML-RARα cleavage creates a modified form of the protein that is important for initiation of this cancer. Further experiments are required to determine the subcellular location at which the cleaveage occurs, and the function of the cleaveage products. NE inhibitors, however, might now be tested as APL therapeutics.