3035 – INTERFERON ALPHA THERAPY ATTENUATES LEUKAEMIC TRANSFORMATION IN JAK2V617F-DRIVEN MPN WITH TRP53-LOSS

Driver mutations in classical myeloproliferative neoplasms (MPNs) (eg. JAK2V617F ) must be initiated and maintained in the haematopoietic stem cell (HSC) pool. Leukaemic transformation to post-MPN AML is characterised by additional genetic lesions and mutations in TP53 are predictive of poor outcomes. Interferon alpha (IFNa) can drive HSC cell cycle entry preferentially in Jak2V617F HSCs resulting in reduced self-renewal capacity. Clinically, IFNa therapy can achieve long-term reductions in JAK2V617F allelic burden. However, the impact of additional mutations on IFNa responses in MPN and transformation to AML remains unclear.

We have generated a single cell RNA sequencing pipeline to monitor the genetic and transcriptional heterogeneity of the HSPC compartment of MPN patients during AML transformation. Transformation is linked with a loss of HSPC hierarchy and devolution to a dominant multipotent progenitor (MPP) state. Using these data to inform parallel murine studies, we demonstrate that haematopoietic expression of Jak2V617F with Trp53-loss is sufficient to drive a fully penetrant leukemia preceded by a distinct MPN disease phase in mice. The resulting AML exhibits a dominant lineage-biased MPP that has leukaemia initiating activity in secondary recipients.

IFNa is still able to induce haematological responses in Jak2V617F MPN with Trp53-loss. However, Trp53-loss also provides a selective advantage for HSCs in the context of chronic exposure to IFNa. Surprisingly, the effects of IFNa on reduced stem cell function are retained in the absence of p53 and chronic administration of IFNa is sufficient to delay leukaemic transformation. Furthermore, IFNa therapy is also effective at preventing disease progression in an established Jak2V617F AML with Trp53-loss. These findings have important implications for the treatment of MPN with TP53 mutations.