Thread by @NicoGagelmann

The wonderful thing about @ASH_hematology Annual Meetings is the fruitful mix of clinic and basic research presentations.

Let's finish off our myelofibrosis coverage about new insights into biology and potential therapeutic targets.

🧵with #ASH22 abstracts

#MedTwitter #mpnsm

Short background:
-driver mutations JAK2, CALR or MPL in 90%
-in concert with epigenetics (eg ASXL1, DNMT3A, SRSF2...)
-aberrant megakaryocytes as quintessence->reduced GATA1 protein expression and plethora of pro-inflammatory cytokines & extra-cellular matrix components 1/15

Now let's go to #ASH22 abstracts covering the following entities of myelofibrosis biology:
D - driver mutations
O - other mutations
C - cell interaction
I - inflammation

For @starwars fans👇2/15

Let's start with the driver mutations, mainly JAK2 and CALR.

For an introduction to JAK2, please see my latest thread:

https://twitter.com/NicoGagelmann/status/1589333141839548424?s=20&t=0GTzDJcmLWiwFQNzmRrT6w

3/15

JAK2 #ASH22:
-conditionally inducible 🐭model for activation+deletion of Jak2VF from endogenous locus in a Dre-rox/Cre-lox recombinase system
-Jak2VF deletion->depletion of HSC
-mutant-selective inhibition offers greater potential than current JAKi ash.confex.com/ash/2022/webpr… 4/15

JAK2/RAS #ASH22:
-RAS mutations: no impact in JAKi naive & worse outcome in JAKi treated patients
-selection of RAS mutations upon JAKi exposure, negatively impacting clinical outcomes
->paradoxical oncogenic mechanism highlights complexity in #mpnsm ash.confex.com/ash/2022/webpr… 5/15

JAK2/SRSF2 #ASH22:
-Srsf2 P95H impairs erythropoiesis in the bone marrow and spleen at multiple differentiation levels (mostly stages II and III)
->phenotypic differences between JAK2-mutant MPN ash.confex.com/ash/2022/webpr… 6/15

Short background to CALR:
-in endoplasmic reticulum (ER)->key component ensuring proper glycoprotein folding & calcium homeostasis
-type 1 (52-bp deletion; c.1092_1143del) & type 2 (5-bp insertion; c.1154_1155insTTGTC) account for >1/2 and ~1/3 of all mutated CALR cases 7/15

CALR #ASH22:
-CALRins5 (type 2) proteins lose chaperone ability & exhibit dominant negative effect over CALR wild-type chaperone function
-tauroursodeoxycholic acid restores ER chaperone capacity->potential therapeutic target ash.confex.com/ash/2022/webpr… 8/15

Other mutations...

HDM2/PPM1D #ASH22:
-key negative regulators of TP53 pathway
- PPM1Di sensitizes MF HSPCs to an HDM2i
->dual targeting has potential to further deplete multiple myelofibrosis HSC clones while allowing persistence of wild-type cells ash.confex.com/ash/2022/webpr… 9/15

Cell interaction.

Mesenchymal cells (MSC) #ASH22:
-comprehensive characterization
-gene not previously linked to fibrosis, HOXB7, identified among highly deregulated genes->most relevant HOXB gene ~ with osteoblast differentiation
-novel axis ash.confex.com/ash/2022/webpr… 10/15

Blast-phase #ASH22:
-surfaceome of transformed MPN
-increased EGFR signaling and altered lipid metabolism
-proof-of-principle for CALR and C3AR1 CAR-T cells
->more in vivo needed ash.confex.com/ash/2022/webpr… 11/15

Metaphyseal stromal cells:
-active bone remodeling co-occurring with fibrotic transformation with skewing of stromal-cell fate towards osteogenesis (WNT activation)
->differences of metaphyseal and diaphyseal macro-niches within bone ash.confex.com/ash/2022/webpr… 12/15

Inflammation #ASH22:
-roadmap of cellular & molecular landscape of normal vs MF bone marrow
-eosinophil-basophil-mast cells & inflammatory fibroblasts as mediators of the inflammatory microenvironment
-galectin-1 as a novel biomarker ash.confex.com/ash/2022/webpr… 13/15

In conclusion, the molecular landscape and its interplay is much more complex than just driver mutations and some others dictating the game. And we only begin to see a glimpse of what the MF microenvironment is affected by. Exciting times in #mpnsm! 14/15

Many of the basic works in #mpnsm are lead and promoted by extraordinary and inspiring groups and researchers, including @rschneiderlab @rosslevinemd @AdamMead_Oxford @beth_psaila @MullallyLab @mpndoc and many more. 15/15

Helpful resources:
onlinelibrary.wiley.com/doi/10.1111/bj…
nejm.org/doi/10.1056/NE…
pubmed.ncbi.nlm.nih.gov/24325359/
pubmed.ncbi.nlm.nih.gov/25326798/