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
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 #mpnsmash.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
Intro:
- caused by protozoa parasites of genus Plasmodium
- transmitted throughout most of the tropics
- in 84 countries and territories
- in 2023, WHO reported 247 million cases (up from 245 million in 2020)
- 619 thousand deaths (down from 625,000 in 2020) 1/
Plasmodium life-cycle:
-female Anopheles mosquitoes acquire parasites from infected person during blood meal
-subsequent human bite, transmit infection to new host👉injection of sporozoites
-infects hepatocytes
-replicates
👉exoerythrocytic merozoite
👉invades erythrocytes 2/
Rule 1: Lead by example
As a mentor, your actions speak louder than words. Demonstrate the ethics, dedication, and passion you wish to instill in your mentees.
Practice what you preach🙏
Rule 2: Listen actively
Effective mentoring starts with listening. Understand your mentee's needs, fears, and aspirations. This builds trust and opens up more honest communication.
Short intro to sickle cell disease (SCD):
-group of inherited red blood cell disorders
-affects ~ 1 in 500 African American and 1 in 36,000 Hispanic American children
-results in anemia
-main clinical feature is acute painful crisis
👉 often requires hospitalization
2/15
Acute pain:
-one of the most common types of vaso-occlusive events in SCD
BUT
-not all patients are in true crisis
BUT
-pain shouldnt be allowed to progress to crisis
AND
-most patients grow with pain, so ask them how severe it is❗️
-do not to delay analgesia
3/15
Intro:
-rare but underestimated bleeding disorder
-lab and clinic similar to inherited form
-usually occurs more frequently in adults with no history of bleeding
-renewed interest
👉association with 🫀disorders (eg aortic stenosis), cancer, autoimmune disease...
2/14
History I - (inherited) VWS:
-1924
-5-year-old girl from 🇫🇮 brought to hospital in Helsinki, seen by physician Erik Adolf von Willebrand
-assessed 66 members of her family
-reported in a 1926 a previously undescribed bleeding disorder, called "Hereditary pseudohemophilia"
3/14
😱Gastrointestinal (GI) manifestations in hematology😱
A short visual 🧵with diagnosis
1/19
Intro:
-lympho-/myeloproliferative disorders
-nodal and/or extranodal
-GI tract one of the most common extranodal sites
-diagnosis of GI hematologic malignancy challenging
👉esp in absence of documented nodal/extranodal disease
👉due to higher incidence of other pathologies
2/19
Importance of imaging:
-although tissue biopsy is often required to reach the definitive diagnosis, imaging plays a crucial role in raising suspicion of underlying hematologic malignancy
-imaging also guides biopsies, staging, and evaluating response to treatment
3/19
History part I:
-1928, Maurice Richter reported generalized swelling of lymph nodes, liver + spleen in a patient with chronic lymphocytic leukemia (CLL)
-due to infiltration by rapidly growing cells
👉termed it generalized reticular cell sarcoma
-patient died after 22 days
2/20
History part II:
-1964, Lortholary described case series of 14 patients with CLL developing malignant reticulopath
👉occurrence of diffuse large B cell lymphoma (DLBCL)
👉named it Richter's transformation (RT)
-DLBCL most common
-also Hodgkin lymphoma, T cell lymphoma
3/20