Inferring the dynamics of mutated hematopoietic stem and progenitor cells induced by IFN alpha in myeloproliferative neoplasms

Classical BCR-ABL-negative myeloproliferative neoplasms (MPNs) are clonal disorders of hematopoietic stem cells (HSCs) caused mainly by recurrent mutations in genes encoding JAK2 (JAK2), calreticulin (CALK), or the thrombopoietin receptor (MPL). Interferon alpha (IFN alpha) has demonstrated some efficacy in inducing molecular remission in MPNs. To determine factors that influence molecular response rate, we evaluated the long-term molecular efficacy of IFN alpha in patients with MPN by monitoring the fate of cells carrying driver mutations in a prospective observational and longitudinal study of 48 patients over more than 5 years. We measured the clonal architecture of early and late hematopoietic progenitors (84 845 measurements) and the global variant allele frequency in mature cells (409 measurements) several times per year. Using mathematical modeling and hierarchical Bayesian inference, we further inferred the dynamics of IFN alpha-targeted mutated HSCs. Our data support the hypothesis that IFN alpha targets JAK2(V617F) HSCs by inducing their exit from quiescence and differentiation into progenitors. Our observations indicate that treatment efficacy is higher in homozygous than heterozygous JAK2(V617F) HSCs and increases with high IFN alpha dose in heterozygous JAK2(V617F) HSCs. We also found that the molecular responses of CALK(m) HSCs to IFN alpha were heterogeneous, varying between type 1 and type 2 CALR(m), and a high dose of IFN alpha correlates with worse outcomes. Our work indicates that the long-term molecular efficacy of IFN alpha implies an HSC exhaustion mechanism and depends on both the driver mutation type and IFN alpha dose.