No abstract

Myeloproliferative neoplasms (MPNs) are blood cancers characterized by excessive production of mature myeloid cells, which result from the acquisition of somatic driver mutations in hematopoietic stem cells (HSCs). Epidemiologic studies indicate a substantial disease heritability that is among the highest known for cancers 1 . However, only a limited set of genetic risk loci have been identified, and the underlying biological mechanisms leading to MPN acquisition remain unexplained. Here, we conducted a large-scale genome-wide association study (3,797 cases and 1,152,977 controls) to identify 17 MPN risk loci (p < 5.0 × 10 −8 ), seven of which have not been previously reported. We find a shared genetic architecture between MPN risk and several hematopoietic traits spanning distinct lineages, an enrichment for risk variants mapping to accessible chromatin in HSCs, and associations of increased MPN risk with longer leukocyte telomere length and other clonal hematopoietic states, collectively implicating HSC function and self-renewal. Gene mapping identifies modulators of HSC biology and targeted variant-to-function assays suggest likely roles for CHEK2 and GFI1B in altering HSC function to confer disease risk. Overall, we demonstrate the power of human genetic studies to illuminate a previously unappreciated mechanism for inherited MPN risk through modulation of HSC function.

Key Points XPO1/CRM1 is upregulated in a BCR-ABL1 kinase-dependent and -independent manner and negatively controls PP2A tumor suppressor activity. KPT-330 antagonizes survival of TKI-resistant Ph+ acute leukemias in vitro, in CML-BC animals, and in a CML-AP patient.

Key Points• The tumor suppressor PP2A is repressed in Jak2 V617F -driven myleoproliferative neoplasms by a Jak2/PI3K/ PKC/SET signaling pathway.• PP2A-activating (eg, FTY720, OSU-2S) but not sphingosine-1-phosphate agonistic (eg, FTY720-P) drugs selectively kill Jak2 V617F1 cells.FTY720 (Fingolimod, Gilenya) is a sphingosine analog used as an immunosuppressant in multiple sclerosis patients. FTY720 is also a potent protein phosphatase 2A (PP2A)-activating drug (PAD). PP2A is a tumor suppressor found inactivated in different types of cancer. We show here that PP2A is inactive in polycythemia vera (PV) and other myeloproliferative neoplasms characterized by the expression of the transforming Jak2 V617F oncogene. PP2A inactivation occurs in a Jak2 V617F dose/kinase-dependent manner through the PI-3Kg-PKC-induced phosphorylation of the PP2A inhibitor SET. Genetic or PADmediated PP2A reactivation induces Jak2 V617F inactivation/downregulation and impairs clonogenic potential of Jak2 V617F cell lines and PV but not normal CD34 1 progenitors.Likewise, FTY720 decreases leukemic allelic burden, reduces splenomegaly, and significantly increases survival of Jak2 V617F leukemic mice without adverse effects. Mechanistically, we show that in Jak2 V617F cells, FTY720 antileukemic activity requires neither FTY720 phosphorylation (FTY720-P) nor SET dimerization or ceramide induction but depends on interaction with SET K209. Moreover, we show that Jak2 V617F also utilizes an alternative sphingosine kinase-1-mediated pathway to inhibit PP2A and that FTY720-P, acting as a sphingosine-1-phosphatereceptor-1 agonist, elicits signals leading to the Jak2-PI-3Kg-PKC-SET-mediated PP2A inhibition. Thus, PADs (eg, FTY720) represent suitable therapeutic alternatives for Jak2

In molar extraction sites without RP, significantly more reduction in ridge height occurred, and the majority of ridge width loss was localized to the buccal aspect. When RP was performed, ridge width loss was not significantly decreased, but the loss was evenly distributed between facial and lingual aspects of the extraction site.