Loss of Function of TET2 Cooperates with Constitutively Active KIT in Murine and Human Models of Mastocytosis

Systemic Mastocytosis (SM) is a clonal disease characterized by abnormal accumulation of mast cells in multiple organs. Clinical presentations of the disease vary widely from indolent to aggressive forms, and to the exceedingly rare mast cell leukemia. Current treatment of aggressive SM and mast cell leukemia is unsatisfactory. An imatinib-resistant activating mutation of the receptor tyrosine kinase KIT (KIT D816V) is most frequently present in transformed mast cells and is associated with all clinical forms of the disease. Thus the etiology of the variable clinical aggressiveness of abnormal mast cells in SM is unclear. TET2 appears to be mutated in primary human samples in aggressive types of SM, suggesting a possible role in disease modification. In this report, we demonstrate the cooperation between KIT D816V and loss of function of TET2 in mast cell transformation and demonstrate a more aggressive phenotype in a murine model of SM when both mutations are present in progenitor cells. We exploit these findings to validate a combination treatment strategy targeting the epigenetic deregulation caused by loss of TET2 and the constitutively active KIT receptor for the treatment of patients with aggressive SM.系统性肥大细胞增多症（Systemic Mastocytosis, SM）是一种克隆性疾病，以多器官内肥大细胞异常蓄积为特征。该病的临床表现差异极大，可表现为惰性病程、侵袭性病程，以及极其罕见的肥大细胞白血病。目前针对侵袭性SM及肥大细胞白血病的治疗效果不尽如人意。受体酪氨酸激酶KIT的伊马替尼耐药性激活突变（KIT D816V）最常见于转化的肥大细胞中，且与该病的所有临床亚型相关。因此，SM中异常肥大细胞临床侵袭性存在差异的病因仍不明确。在侵袭性SM的原发性人类样本中，TET2存在突变，这提示其可能在疾病修饰中发挥作用。本研究证实，KIT D816V与TET2功能缺失在肥大细胞转化过程中存在协同作用；并且在祖细胞同时携带这两种突变的SM小鼠模型中，观察到了更具侵袭性的表型。基于上述发现，本研究验证了一种联合治疗策略：针对TET2缺失引发的表观遗传失调以及组成型激活的KIT受体，用于治疗侵袭性SM患者。