Thread by @MullallyLab

We studied newly diagnosed patients with ET and PV,
reconstructing the lineage history & differentiation trajectories of individual JAK2V617F HSC - here is our preprint will full details #MPNsm
biorxiv.org/content/10.110…

Our work will be presented by Debra Van Egeren, a grad student @Harvard in an oral abstract @ASH_Hematology #ASH20. This is a team effort across @DanaFarber @BrighamHeme @MGHCancerCenter @df_hcc @BCHStemCell @embl ash.confex.com/ash/2020/webpr…

3. We performed combined single-cell genotyping & transcriptomic profiling on CD34+ enriched BM from newly diagnosed patients with ET and PV, plus whole genome sequencing for lineage tracing of JAK2-mutant HSC.

4. We found JAK2V617F mutation arises in a single HSC decades before diagnosis, including within first decade of life – any thoughts @bloodgenes?

5. JAK2-mutant HSPCs have a meg-erythroid fate bias but JAK2-mutant allele fraction varies within myeloid compartment within same patient – virtually all erythroid progenitor cells are JAK2-mutant even in ET!

6. Peripheral blood JAK2V617F allele fraction does not reflect mutation frequency in HSC nor does it accurately reflect JAK2-mutant allele fraction in meg-erythroid lineage

7.We identified JAK2V617F-specific transcriptional changes – intriguingly newly diagnosed PV patients have increased SLAMF7 expression on CD14 cells – a cell surface protein expressed on fibrocytes & targetable with elotuzumab

8. We think our work has implications for MPN treatment (e.g. V617F mutant-specific inhibitors), potential for MPN prevention (long pre-clinical phase), implications for V617F allele burden monitoring & for thrombosis (cell-intrinsic effects in RBC, PLTs – lots to do @MPN_RF !

9. So many people to thank especially our patients who participated in the study & all the physicians & researchers including in particular Dr. Sahand Hormoz @DanaFarber who led this work. Also @GabyHobbs @LuskinMarlise @Baransel_Kamaz & all those co-authors not on Twitter!

10. Finally, thanks to all who contributed funding to this work including @NIGMS @nih_nhlbi @LLSusa @CureCancerNow @DanaFarber @NSF @embl @MPN_RF