Inferring the dynamic of mutated hematopoietic stem and progenitor cells induced by IFNα 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 (CALR), or the thrombopoietin receptor (MPL). Interferon a
(IFNa) 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 IFNa 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 IFNa-targeted mutated HSCs. Our data
support the hypothesis that IFNa targets JAK2V617F HSCs by inducing their exit from quiescence and differentiation
into progenitors. Our observations indicate that treatment efficacy is higher in homozygous than heterozygous
JAK2V617F HSCs and increases with high IFNa dose in heterozygous JAK2V617F HSCs. We also found that the molecular responses of CALRm HSCs to IFNa were heterogeneous, varying between type 1 and type 2 CALRm, and a high
dose of IFNa correlates with worse outcomes. Our work indicates that the long-term molecular efficacy of IFNa
implies an HSC exhaustion mechanism and depends on both the driver mutation type and IFNa dose