FLT3-ITD cooperates with inv(16) to promote progression to acute myeloid leukemia
FLT3-ITD cooperates with inv(16) to promote progression to acute myeloid leukemia
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DOI：
10.1182/blood-2006-06-030312
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发表时间：
2008-02-01
期刊：
影响因子：
20.3
通讯作者：
Klug, Christopher A.
中科院分区：
文献类型：
--
作者：
Kim, Hyung-Gyoon;Kojima, Kyoko;Klug, Christopher A.
16号染色体inv（16）（p13 q22）倒位是急性髓系白血病（AML）中最常见的细胞遗传学异常之一。inv（11 6）将核心结合因子（CBF）β亚基与平滑肌肌球蛋白重链（SMMHC）的卷曲螺旋杆结构域融合。在没有继发突变的情况下，小鼠中CBF β-SMMHC的表达不会促进AML。在几乎70%的病例中，inv（16）患者样本在N-RAS、K-RAS或受体酪氨酸激酶c-KIT和FLT 3中也具有互斥激活突变。为了测试FLT 3的激活突变（FLT 3-ITD）是否会与CBF β-SMMHC合作促进AML，我们在用于重建致死性辐射小鼠的造血祖细胞中共表达两种突变。对移植动物的分析显示，对骨髓和外周血中表达CBF β-SMMHC-FLT 3-ITD的细胞具有强选择性。与仅移植CBF β-SMMHC表达细胞的动物相比，FLT 3-ITD进一步限制了早期髓样分化，并早在移植后2.5周就促进了原始成髓细胞的外周化。FLT 3-ITD还加速了所有CBF β-SMMHC/FLT 3-ITD重建动物的疾病进展，这些动物在3至5个月内死于高度侵袭性和可移植的AML。这些结果表明，在inv（16）相关AML的动物模型中，FLT 3激活突变可与CBF β-SMMHC协同作用。
The inversion of chromosome 16 in the inv(16)(p13q22) is one of the most frequent cytogenetic abnormalities observed in acute myeloid leukemia (AML). The inv(11 6) fuses the core binding factor (CBF) beta subunit with the coiled-coil rod domain of smooth muscle myosin heavy chain (SMMHC). Expression of CBF beta-SMMHC in mice does not promote AML in the absence of secondary mutations. Patient samples with the inv(16) also possess mutually exclusive activating mutations in either N-RAS, K-RAS, or the receptor tyrosine kinases, c-KIT and FLT3, in almost 70% of cases. To test whether an activating mutation of FLT3 (FLT3-ITD) would cooperate with CBF beta-SMMHC to promote AML, we coexpressed both mutations in hematopoietic progenitor cells used to reconstitute lethally irradiated mice. Analysis of transplanted animals showed strong selection for CBF beta-SMMHC-FLT3-ITD-expressing cells in bone marrow and peripheral blood. Compared with animals transplanted with only CBF beta-SMMHC-expressing cells, FLT3-ITD further restricted early myeloid differentiation and promoted peripheralization of primitive myeloblasts as early as 2.5 weeks after transplantation. FLT3-ITD also accelerated disease progression in all CBF beta-SMMHC/FLT3-ITD-reconstituted animals, which died of a highly aggressive and transplantable AML within 3 to 5 months. These results indicate that FLT3-activating mutations can cooperate with CBF beta-SMMHC in an animal model of inv(16)-associated AML.