Yao H, Ma Y, Hong Z, Zhao L, Monaghan S A, Hu M-C, Huang L J
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Leukemia. 2017 Oct;31(10):2122-2131. doi: 10.1038/leu.2017.1. Epub 2017 Jan 6.
Janus tyrosine kinase 2 (JAK2) mediates downstream signaling of cytokine receptors in all hematological lineages, yet constitutively active JAK2 mutants are able to drive selective expansion of particular lineage(s) in myeloproliferative neoplasm (MPN). The molecular basis of lineage specificity is unclear. Here, we show that three activating JAK2 mutants with similar kinase activities in vitro elicit distinctive MPN phenotypes in mice by differentially expanding erythroid vs granulocytic precursors. Molecularly, this reflects the differential binding of JAK2 mutants to cytokine receptors EpoR and GCSFR in the erythroid vs granulocytic lineage and the creation of unique receptor/JAK2 complexes that generate qualitatively distinct downstream signals. Our results demonstrate that activating JAK2 mutants can differentially couple to selective cytokine receptors and change the signaling repertoire, revealing the molecular basis for phenotypic differences elicited by JAK2 (V617F) or mutations in exon 12. On the basis of these findings, receptor-JAK2 interactions could represent new targets of lineage-specific therapeutic approaches against MPN, which may be applicable to other cancers with aberrant JAK-STAT signaling.
Janus酪氨酸激酶2（JAK2）介导所有血液谱系中细胞因子受体的下游信号传导，然而组成型活性JAK2突变体能够驱动骨髓增殖性肿瘤（MPN）中特定谱系的选择性扩增。谱系特异性的分子基础尚不清楚。在这里，我们表明，三种在体外具有相似激酶活性的激活型JAK2突变体，通过差异地扩增红系与粒系前体细胞，在小鼠中引发独特的MPN表型。在分子水平上，这反映了JAK2突变体在红系与粒系谱系中与细胞因子受体EpoR和GCSFR的差异结合，以及产生独特的受体/JAK2复合物，这些复合物产生性质不同的下游信号。我们的结果表明，激活型JAK2突变体可以与选择性细胞因子受体差异偶联并改变信号传导谱，揭示了由JAK2（V617F）或第12外显子突变引起的表型差异的分子基础。基于这些发现，受体-JAK2相互作用可能代表针对MPN的谱系特异性治疗方法的新靶点，这可能适用于其他具有异常JAK-STAT信号传导的癌症。
