Cbfb/Runx1 repression-independent blockage of differentiation and accumulation of Csf2rb-expressing cells by Cbfb-MYH11
Cbfb/Runx1 repression-independent blockage of differentiation and accumulation of Csf2rb-expressing cells by Cbfb-MYH11
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DOI：
10.1182/blood-2009-06-227413
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发表时间：
2010-02-18
期刊：
影响因子：
20.3
通讯作者：
Liu, P. Paul
中科院分区：
文献类型：
--
作者：
Hyde, R. Katherine;Kamikubo, Yasuhiko;Liu, P. Paul
已知CBFB-MYH 11是由人急性髓性白血病中16号染色体倒位产生的融合基因，是致癌转化的原因。然而，CBFB-MYH11启动白血病发生的机制尚不清楚。先前发表的报告显示，CBFB-MYH11主要抑制RUNX1和CBFB，并且这种抑制被认为是白血病发生的机制。在这里，我们表明，Cbfb-MYH11引起的Cbfb/Runx1抑制在原始和永久造血独立的缺陷。在原始造血过程中，Cbfb-MYH11延迟分化，其特征在于持续表达Gata2、Il1rl1和Csf2rb，这是在Cbfb和Runx1敲除小鼠中未发现的表型。骨髓中Cbfb-MYH11的表达诱导白血病前期小鼠中表达Csf2rb的异常祖细胞样细胞的积累。在大多数人和小鼠CBFB-MYH11（+）白血病样本中检测到所有3种基因的表达。有趣的是，虽然我们的Cbfb-MYH11敲入小鼠中的大多数白血病细胞是Csf2rb（+），但Cbfb-MYH11（+）前白血病祖细胞和白血病起始细胞不表达Csf2rb。因此，Csf2rb可用作负选择标记物以富集来自Cbfb-MYH 11小鼠的白血病前祖细胞和白血病起始细胞。这些结果表明，Cbfb/Runx1抑制独立的活动有助于白血病的Cbfb-MYH11。（血。2010; 115：1433 - 1443）
It is known that CBFB-MYH11, the fusion gene generated by inversion of chromosome 16 in human acute myeloid leukemia, is causative for oncogenic transformation. However, the mechanism by which CBFB-MYH11 initiates leukemogenesis is not clear. Previously published reports showed that CBFB-MYH11 dominantly inhibits RUNX1 and CBFB, and such inhibition has been suggested as the mechanism for leukemogenesis. Here we show that Cbfb-MYH11 caused Cbfb/Runx1 repression-independent defects in both primitive and definitive hematopoiesis. During primitive hematopoiesis, Cbfb-MYH11 delayed differentiation characterized by sustained expression of Gata2, Il1rl1, and Csf2rb, a phenotype not found in Cbfb and Runx1 knockout mice. Expression of Cbfb-MYH11 in the bone marrow induced the accumulation of abnormal progenitor-like cells expressing Csf2rb in preleukemic mice. The expression of all 3 genes was detected in most human and murine CBFB-MYH11(+) leukemia samples. Interestingly, Cbfb-MYH11(+) preleukemic progenitors and leukemia-initiating cells did not express Csf2rb, although the majority of leukemia cells in our Cbfb-MYH11 knockin mice were Csf2rb(+). Therefore Csf2rb can be used as a negative selection marker to enrich preleukemic progenitor cells and leukemia-initiating cells from Cbfb-MYH11 mice. These results suggest that Cbfb/Runx1 repression-independent activities contribute to leukemogenesis by Cbfb-MYH11. (Blood. 2010; 115: 1433-1443)