Schematic of novel therapies in development for the treatment of MPNs. (A) Targeting the HSC and microenvironment. JAK2V617F–mutated HSCs show clonal dominance over wild-type HSCs. Interferon preferentially targets JAK2-mutated HSCs to induce exit from quiescence and promote terminal myeloid differentiation, resulting in preferential depletion of JAK2-mutated HSCs. The expanded myeloid clone also disrupts the BM microenvironment through secretion of inflammatory mediators. Novel therapies targeting inflammation and profibrotic cytokines may delay or prevent the progression of early MPNs to MF. (B) Targeting cell signaling, epigenetics, and apoptosis. MPNs are characterized by activated JAK/STAT signaling. Multiple signaling pathways are activated downstream of mutant JAK2 and represent targets for therapeutic intervention. (C) Novel therapies targeting CALR-mutated MPNs. Novel therapies in preclinical development against CALR-mutated MPNs include antibodies to block mutant CALR on the cell surface and peptides to disrupt intracellular MPL/mutant CALR binding. (D) Immune therapies targeting CALR-mutated MPNs. Vaccination strategies to induce T-cell–directed immune activation against CALR-mutated clones take advantage of the mutant CALR C-terminus neoepitopes generated by CALR mutations. APC, antigen-presenting cell; DT, diphtheria toxin; ER, endoplasmic reticulum; IFN, interferon; MUT, mutated; P, phosphorylated; TCR, T-cell receptor; WT, wild-type. Professional illustration by Patrick Lane, ScEYEnce Studios.