Leukemogenic potency of the novel FLT3-N676K mutant
Leukemogenic potency of the novel FLT3-N676K mutant
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DOI：
10.1007/s00277-016-2616-z
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发表时间：
2016-04-01
影响因子：
3.5
通讯作者：
Li, Zhixiong
中科院分区：
文献类型：
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作者：
Huang, Kezhi;Yang, Min;Li, Zhixiong
最近在6%的inv新发急性髓性白血病（AML）患者中发现了FLT 3激酶结构域-1内的新型FMS样酪氨酸激酶3（FLT 3）-N676 K点突变（16）。由于FLT 3-N676 K几乎只在inv（16）AML中遇到，因此我们研究了FLT 3-N676 K的转化潜力，FLT 3-N676 K与核心结合因子-平滑肌肌球蛋白重链之间的协同作用，（CBF-SMMHC）（由inv（16）嵌合基因CBFB-MYH 11编码）诱导急性白血病，并测试了FLT 3-N676 K阳性白血病细胞对FLT 3抑制剂的敏感性。骨髓32 D细胞中FLT 3-N676 K的逆转录病毒表达诱导了同基因C3 H/HeJ小鼠的AML（n = 11/13，中位潜伏期58天），其转化活性与FLT 3-内部串联重复（ITD）（n = 8/8）、FLT 3-TKD D835 Y（n = 8/9）和FLT 3-ITD-N676 K（n = 9/9）突变相似。移植FLT 3-N676 K转导的原代造血祖细胞的14只C57 BL/6 J小鼠中有3只（21.4%）发生急性白血病（潜伏期为68、77和273天），而在包括FLT 3-ITD在内的对照组中未观察到血液学恶性肿瘤。此外，在三个独立的实验中，FLT 3-N676 K/CBF-SMMHC的共表达没有促进急性白血病（n = 16）。与FLT 3-ITD相比，FLT 3-N676 K诱导FLT 3更高的活化，并且倾向于触发更强的MAPK和AKT磷酸化。重要的是，在没有ITD突变的情况下，携带FLT 3-N676 K突变体的白血病细胞对FLT 3抑制剂AC 220和crenolanib高度敏感，crenolanib甚至保留了针对AC 220耐药FLT 3-ITD-N676 K突变体的活性。总之，FLT 3-N676 K突变体在体内转化鼠造血干/祖细胞是有效的。这是第一个报告的急性白血病诱导的激活FLT 3突变的C57 BL/6 J小鼠。此外，研究FLT 3-N676 K突变诱导的白血病发生的分子机制和FLT 3抑制剂在FLT 3-N676 K阳性AML中的临床评价的进一步实验似乎是必要的。
The novel FMS-like tyrosine kinase 3 (FLT3)-N676K point mutation within the FLT3 kinase domain-1 was recently identified in 6 % of de novo acute myeloid leukemia (AML) patients with inv(16). Because FLT3-N676K was encountered almost exclusively in inv(16) AML, we investigated the transforming potential of FLT3-N676K, the cooperation between FLT3-N676K and core binding factor -smooth muscle myosin heavy chain (CBF-SMMHC) (encoded by the inv(16) chimeric gene CBFB-MYH11) in inducing acute leukemia, and tested the sensitivity of FLT3-N676K-positive leukemic cells to FLT3 inhibitors. Retroviral expression of FLT3-N676K in myeloid 32D cells induced AML in syngeneic C3H/HeJ mice (n = 11/13, median latency 58 days), with a transforming activity similar to FLT3-internal tandem duplication (ITD) (n = 8/8), FLT3-TKD D835Y (n = 8/9), and FLT3-ITD-N676K (n = 9/9) mutations. Three out of 14 (21.4 %) C57BL/6J mice transplanted with FLT3-N676K-transduced primary hematopoietic progenitor cells developed acute leukemia (latency of 68, 77, and 273 days), while no hematological malignancy was observed in the control groups including FLT3-ITD. Moreover, co-expression of FLT3-N676K/CBF-SMMHC did not promote acute leukemia in three independent experiments (n = 16). In comparison with FLT3-ITD, FLT3-N676K induced much higher activation of FLT3 and tended to trigger stronger phosphorylation of MAPK and AKT. Importantly, leukemic cells carrying the FLT3-N676K mutant in the absence of an ITD mutation were highly sensitive to FLT3 inhibitors AC220 and crenolanib, and crenolanib even retained activity against the AC220-resistant FLT3-ITD-N676K mutant. Taken together, the FLT3-N676K mutant is potent to transform murine hematopoietic stem/progenitor cells in vivo. This is the first report of acute leukemia induced by an activating FLT3 mutation in C57BL/6J mice. Moreover, further experiments investigating molecular mechanisms for leukemogenesis induced by FLT3-N676K mutation and clinical evaluation of FLT3 inhibitors in FLT3-N676K-positive AML seem warranted.