Human Cancer Genetics Program, Department of Molecular Virology Immunology and Medical Genetics.
Blood. 2013 Sep 12;122(11):1923-34. doi: 10.1182/blood-2013-03-492181. Epub 2013 Aug 7.
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-3Kγ-PKC-induced phosphorylation of the PP2A inhibitor SET. Genetic or PAD-mediated PP2A reactivation induces Jak2(V617F) inactivation/downregulation and impairs clonogenic potential of Jak2(V617F) cell lines and PV but not normal CD34(+) 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-phosphate-receptor-1 agonist, elicits signals leading to the Jak2-PI-3Kγ-PKC-SET-mediated PP2A inhibition. Thus, PADs (eg, FTY720) represent suitable therapeutic alternatives for Jak2(V617F) MPNs.
FTY720（芬戈莫德，Gilenya）是一种鞘氨醇类似物，在多发性硬化症患者中用作免疫抑制剂。FTY720 也是一种有效的蛋白磷酸酶 2A（PP2A）激活药物（PAD）。PP2A 是一种肿瘤抑制因子，在不同类型的癌症中失活。我们在这里表明，PP2A 在真性红细胞增多症（PV）和其他由表达转化 Jak2（V617F）癌基因的骨髓增殖性肿瘤中失活。PP2A 的失活通过 PI-3Kγ-PKC 诱导的 PP2A 抑制剂 SET 的磷酸化以 Jak2（V617F）剂量/激酶依赖性方式发生。遗传或 PAD 介导的 PP2A 再激活诱导 Jak2（V617F）失活/下调，并损害 Jak2（V617F）细胞系和 PV 的集落形成潜力，但不影响正常的 CD34+祖细胞。同样，FTY720 降低白血病等位基因负担，减少脾肿大，并显著增加 Jak2（V617F）白血病小鼠的存活率，而没有不良反应。在机制上，我们表明在 Jak2（V617F）细胞中，FTY720 的抗白血病活性既不需要 FTY720 磷酸化（FTY720-P）也不需要 SET 二聚化或神经酰胺诱导，而是依赖于与 SET K209 的相互作用。此外，我们表明 Jak2（V617F）还利用替代的鞘氨醇激酶 1 介导的途径来抑制 PP2A，并且 FTY720-P 作为一种 1-磷酸鞘氨醇受体-1 激动剂，引发导致 Jak2-PI-3Kγ-PKC-SET 介导的 PP2A 抑制的信号。因此，PAD（例如，FTY720）代表 Jak2（V617F）MPN 的合适治疗替代方案。
