Potent co-operation between the NUP98-NSD1 fusion and the FLT3-ITD mutation in acute myeloid leukemia induction
Potent co-operation between the NUP98-NSD1 fusion and the FLT3-ITD mutation in acute myeloid leukemia induction
复制标题
DOI：
10.3324/haematol.2013.100917
复制
发表时间：
2014-09-01
期刊：
影响因子：
10.1
通讯作者：
Schwaller, Juerg
中科院分区：
文献类型：
--
作者：
Thanasopoulou, Angeliki;Tzankov, Alexandar;Schwaller, Juerg
NUP98-NSD1融合是t(5；11)(q35；p15.5)染色体易位的产物，是细胞遗传学正常的儿童急性髓系白血病中最常见的遗传改变之一，与预后不良有关。在超过70%的NUP98-NSD1阳性患者中发现了Flt3-ITD激活突变的共存。为了解决功能协同作用，我们确定了逆转录病毒表达的NUP98-NSD1和Flt3-ITD在小鼠中的转化潜力。NUP98-NSD1的表达为小鼠提供了依赖于菌株的、异常的骨髓前体细胞自我更新能力。共表达Flt3-ITD在体外可促进细胞增殖并维持自我更新。将共表达NUP98NSD1和Flt3-ITD的永生化祖细胞移植到小鼠体内，小鼠在很短的潜伏期后发生了急性髓系白血病。相反，NUP98NSD1和Flt3-ITD单独转导的细胞都不能启动白血病。有趣的是，据报道，携带NUP98-NSD1的患者中，Flt3-ITD与野生型Flt3mRNA表达比率的增加与flt3信号的增加与快速诱发疾病有关。相比之下，NUP98-NSD1融合基因或其建议的靶点HoxA5、HoxA7、HoxA9或HoxA10的表达水平在不同发病潜伏期的动物之间没有差异。最后，共表达NUP98-NSD1和Flt3-ITD的白血病细胞对小分子Flt3抑制剂非常敏感，这突显了异常的flt3信号对NUP98-NSD1阳性白血病的重要性，并提出了可能改善患者预后的新的治疗方法。
The NUP98-NSD1 fusion, product of the t(5;11)(q35;p15.5) chromosomal translocation, is one of the most prevalent genetic alterations in cytogenetically normal pediatric acute myeloid leukemias and is associated with poor prognosis. Co-existence of an FLT3-ITD activating mutation has been found in more than 70% of NUP98-NSD1-positive patients. To address functional synergism, we determined the transforming potential of retrovirally expressed NUP98-NSD1 and FLT3-ITD in the mouse. Expression of NUP98-NSD1 provided mouse strain-dependent, aberrant self-renewal potential to bone marrow progenitor cells. Co-expression of FLT3-ITD increased proliferation and maintained self-renewal in vitro. Transplantation of immortalized progenitors co-expressing NUP98NSD1 and FLT3-ITD into mice resulted in acute myeloid leukemia after a short latency. In contrast, neither NUP98NSD1 nor FLT3-ITD single transduced cells were able to initiate leukemia. Interestingly, as reported for patients carrying NUP98-NSD1, an increased Flt3-ITD to wild-type Flt3 mRNA expression ratio with increased FLT3-signaling was associated with rapidly induced disease. In contrast, there was no difference in the expression levels of the NUP98-NSD1 fusion or its proposed targets HoxA5, HoxA7, HoxA9 or HoxA10 between animals with different latencies to develop disease. Finally, leukemic cells co-expressing NUP98-NSD1 and FLT3-ITD were very sensitive to a small molecule FLT3 inhibitor, which underlines the significance of aberrant FLT3 signaling for NUP98-NSD1-positive leukemias and suggests new therapeutic approaches that could potentially improve patient outcome.