Roychoudhuri Lab

Insane paper alert! Interferon is the one therapy that can actually deplete the mutant stem cells in myeloproliferative neoplasms, the blood cancers where the marrow keeps overproducing one lineage or another. The standard explanation for how it works was fairly mechanical. It pushes the mutant cells into the cell cycle, they divide, and eventually they exhaust or lose ground. Clean enough to teach. Lama et al. pulls it apart, and it can do that because of a set of single-cell methods that read out the mutation, the transcriptome, the surface proteins and the chromatin in the same cell, so the healthy stem cells sit inside the same patient as a built-in control, right next to their mutant neighbors. What they see is that interferon does not do one thing to a stem cell, it does two opposite things at once. Part of the stem pool is driven into an inflammatory myeloid progenitor state nobody had really described before, running on AP-1 and NF-κB. Another part is pushed toward lymphoid output. That lymphoid arm is easy to overlook, but it seems to be doing the clinical work, offsetting the myeloid overproduction that defines the disease, which is likely why counts normalize even in patients whose mutant fraction barely moves. Interestingly, the result that carries the paper is a negative one. If fitness ran on proliferation, the clones cycling fastest under interferon should be the ones whose fate you could predict. But the mutant cells cycled faster than the healthy ones throughout, before treatment and during it, and that gap predicted nothing about which clones expanded and which collapsed. What predicted it was whether a clone would follow that inflammatory myeloid path out of the stem state. The ones that resisted held on or grew. The ones that went along got cleared. So the drug is not really wearing the clone down. It is holding open an exit from the stem cell state, and resistance amounts to declining to take it. The mutations tilt the cell's transcription-factor wiring, PU.1 in particular, so mutant and healthy cells read the same interferon signal differently, and the mutant ones tend to sit tighter in the stem compartment…and the same resistance signature turns up in DNMT3A clonal hematopoiesis, so it is probably not tied to one mutation or one disease. If a clone survives by refusing to differentiate, killing it is beside the point. You would have to take the exit away, so it has to leave the stem state whether it resists or not, and I don't know what that looks like yet, or how much of this same quiet sorting runs in ordinary aging marrow where no one is being treated at all. @AnnaEnim @landau_lab and many more rockstars! #MyeloproliferativeNeoplasms #Hematology #StemCellBiology #SingleCell #Interferon Nature Genetics, doi.org/10.1038/s41588-026-0…