JAK2 and MPL are two main regulators of TPO-induced megakaryopoiesis

 

Megakaryocytes (MKs) are derived from the hematopoietic stem cells (HSCs) through a 2-step process: proliferation stage that generates MK precursors, and differentiation stage that produces MKs without further proliferation. The 2-step process, called megakaryopoiesis, regulated by thrombopoietin (TPO), which binds to myeloproliferative leukemia (MPL), then activates multiple signaling molecules. One of the most associated molecules is janus kinase 2 (JAK2). Besancenot et al. demonstrated that the protein levels of JAK2 and MPL determine TPO-induced megakaryopoiesis. This article was published on Blood.

 

In this study, researchers used human megakaryoblastic UT7 cells which can express MPL. Those cells abnormally accumulate MKs, suggesting a escape from the proliferation arrest in terminal steps of differentication. In UT7-MPL cells, when JAK2 or MPL expressed at low level, the TPO-induced cell proliferation and antiproliferation were suppressed in proliferation and differentiation stages, respectively. However, when JAK2 and MPL were at higher expression levels, TPO enhanced cell-cycle arrest and MK differentiation. Moreover, researchers found suboptimal doses of JAK2 inhibitors elevated the production of MKs both in vitro and in vivo. The observation can be explained by the model that JAK2 is the downstream signaling molecule of TPO receptor MPL.

 

Reference:
Blood. 2014 Sep 25;124(13):2104-2115.

Related Products

Cat.No.	Product Name	Information
S8057	Pacritinib	Pacritinib is a potent and selective inhibitor of Janus Kinase 2 (JAK2) and Fms-Like Tyrosine Kinase-3 (FLT3) with IC50s of 23 and 22 nM in cell-free assays, respectively. Phase 3.
S2736	Fedratinib (TG101348)	Fedratinib (SAR302503, TG101348) is a selective inhibitor of JAK2 with IC50 of 3 nM in cell-free assays, 35- and 334-fold more selective for JAK2 versus JAK1 and JAK3. Fedratinib also inhibits FMS-like tyrosine kinase 3 (FLT3) and RET (c-RET) with IC50 of 15 nM and 48 nM, respectively. Fedratinib has potential antineoplastic activity. Fedratinib inhibits proliferation and induces apoptosis. Phase 2.

Related Targets

JAK