New pathways and molecular mechanisms in MPN

Overview of Presentations with access to videos on demand (EHA subscription needed)

LINKS TO ABSTRACTS:

The study authors conclude that JAK2-mutant HSCs have inherently higher cycling compared to wildtype-HSCs. However, they identify for the first time a dormant sub-fraction of mutant HSCs within the bone marrow. These dormant HSCs may be responsible for disease propagation and relapse after therapy. In support of this, dormant HSCs were unaffected by Fedratinib treatment in mice where hematologic parameters had been normalized, while peg-IFNα was found to eliminate the dormant mutant HSCs. These data provide a new model to explore novel strategies to eliminate therapy-resistant HSCs in the setting of JAK2 mutated MPNs.

 

Presentation ID p419-2

(S196) CALR FRAMESHIFT MUTATIONS ACCELERATE MATURATION OF MEGAKARYOCYTES IN MPN PATIENT-DERIVED IPS CELLS

Presenter: Kathrin Olschok, Aachen, Germany

The study authors demonstrate that het and hom CALRins5‐ and del52‐mutated iPS cells recapitulate features observed in ET and PMF patients, such as an increased number of MKs, and that this can be reversed by repair of the mutation, suggesting that mutant CALR is responsible for these effects. Mechanistically, their data show that mutant CALR induces an accelerated maturation process of MKs, which is in line with accelerated platelet turnover seen in ET and PMF patients.

 

The study authors demonstrate with their data an essential role for TYK2 in CALR-mutant but not JAK2V617F- mutant MPN cells. This suggests pharmacologic TYK2 inhibition as a novel promising treatment approach in CALR- mutant MPNs.

 

The study authors show that MPN NSC resides in a CD34+/CD38−fraction of the malignant clone and displays a unique phenotype, including immune checkpoint molecules, cytokine receptors, and other target antigens. Their results should support the isolation of MPN NSC and the development of NSC-eradicating therapies in MPN.

 

Presentation ID p419-5

(S199) BH3-MIMETICS AND AZACITIDINE SHOW SYNERGISTIC EFFECTS ON JUVENILE MYELOMONOCYTIC LEUKEMIA

Presenter: Naile Koleci, Germany

The study authors conclude that their study confirms that the effects of azacitidine are significantly increased by adding BH3-mimetics. Such combination strategies will be especially important for those patients that are resistant to azacitidine monotherapy.