JAK2V617F allele dosage and HSC transcriptional priming

Current understanding

JAK2V617F allele dosage (heterozygous vs. homozygous/copy-neutral LOH) appears to act as a rheostat shaping hematopoietic stem cell transcriptional state, with single-cell multi-omic profiling (e.g., GIFT) revealing a gradient of interferon-associated transcriptional programs that scales with mutant allele dose. This dose-dependent IFN-program gradient is proposed to prime HSCs toward divergent MPN phenotypes (ET vs. PV vs. PMF), reframing allele burden as a continuous mechanistic variable rather than a binary mutation status. Evidence is currently preclinical, resting on single-cell genotype+transcriptome data in primary MPN samples.

Evidence log

• February 3 — Prelude Therapeutics Receives FDA Clearance of Investigational New Drug Application (IND) for PRT12396, a Mutant-selective JAK2V617F Inhibitor: cross-connection with jak-stat-signaling: Mutant-selective JH2-directed JAK2V617F inhibition (PRT12396) is mechanistically positioned to preferentially suppress allele-dose-dependent mutant JAK2 signaling while sparing wild-type JAK2, linking the dose-graded HSC transcriptional priming phenotype to a therapeutic strategy that could selectively collapse the high-allele-burden compartment. (novelty: 4)

Open questions

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