Major progress in understanding progression in chronic myeloid leukemia
Authors: Jerry Radich
Journal: The Journal of Experimental Medicine (2015)

The Journal of Experimental Medicine At last, a mouse model of the natural history of chronic myeloid leukemia (CML) has been elegantly engineered.CML is hardly a public health menace, occurring in only 1-2 per 100,000 people.Nonetheless, the disease is the "poster child" of genetically based diagnosis and treatment, as all cases of CML have the BCR-ABL translocation, which is both a diagnostic marker of the disease and a target for tyrosine kinase inhibitor (TKI) therapy.CML is usually diagnosed in the so-called chronic phase, characterized by an expansion of circulating mature myeloid cells.Without treatment, all CML cases will eventually accumulate new mutational events, progressing first into accelerated phase and then to a fatal blast phase.The advent of TKI therapy has made a major impact on the natural history of chronic phase disease, and few patients now progress on therapy.However, some do, and still other patients actually present with advanced phase disease.For these patients, therapeutic options are limited and generally ineffective.The genetic "clock" that drives CML progression is unknown, and this limits development of diagnostic tools to predict progression and therapeutic options to block or treat it.A major part of this limitation is the lack of mouse models of CML that accurately simulate human CML.Most mouse CML models quickly develop an acute leukemia, often of the lymphoid lineage (unlike CML blast crisis, which is predominantly myeloid), or stay in a chronic phase.In this issue, Giotopoulos et al. provide a major contribution to the field by developing a cleverly engineered mouse model that quite faithfully duplicates human CML.Their mouse model has both inducible BCR-ABL and "Sleeping Beauty" transposon elements, allowing them to first activate BCR-ABL (mimicking chronic phase), and later to activate transposon-based insertional mutagenesis (mimicking progression).The model shows many features of human CML, including progression from chronic phase to a predominantly myeloid blast crisis, expansion of the hematopoetic stem cell and progenitor cell compartments, and similar changes in gene expression from chronic to blast phase as those reported in human samples (much to the relief of both mouse and human investigators!).The authors find a role for pathways that are potentially targetable by existing and investigational agents, including ERG, MYC, MEK, RAF, and JAK1/2.This will likely lead to the rapid development of mouse models in which to study whether such agents can either treat or prevent blast crisis.Because the therapeutic options for humans with advanced phase are severely limited (with curative potential limited to allogeneic transplantation), the findings from this paper will also likely quickly lead to the study of these pathways in patients with advanced phase disease, with possible intervention in those cases where activation can be demonstrated.The outcome for patients with blast crisis has remained relatively static for decades.The findings from this strong manuscript suggest that may soon change.