EVI1 and GATA2 misexpression induced by inv(3)(q21q26) contribute to megakaryocyte-lineage skewing and leukemogenesis
EVI1 and GATA2 misexpression induced by inv(3)(q21q26) contribute to megakaryocyte-lineage skewing and leukemogenesis
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DOI：
10.1182/bloodadvances.2019000978
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发表时间：
2020-04-28
期刊：
影响因子：
7.5
通讯作者：
Yamamoto, Masayuki
中科院分区：
文献类型：
--
作者：
Yamaoka, Ayaka;Suzuki, Mikiko;Yamamoto, Masayuki
3q21和3q26之间的染色体重排导致高危急性髓系白血病(AML)，这通常与血小板和巨核细胞(Mk)数量增加有关。3Q重排将GATA2增强子重新定位在EVI1(或Mecom)位点附近，导致EVI1过表达和GATA2单倍体不足。然而，解释这两个基因的错误表达如何单独促进白血病发生的机制尚不清楚。为了阐明EVI1和GATA2错误表达导致的分化缺陷的特征和确定白血病细胞的细胞来源，我们建立了一个系统来监测3Q重排AML模型小鼠中inv(3)等位基因驱动的EVI1和Gata2的表达。在弗兰克白血病发病前，骨髓中出现了高度诱导EVI1和Gata2的细胞群。该种群获得了连续集落形成的潜力。由于造血干/祖细胞(HSPC)和MKs在这一特殊人群中丰富，我们分析了EVI1和GATA2对HSPC和MK的独立贡献。我们发现，inv(3)驱动的EVI1促进了Mk偏向和髓系偏向的祖细胞、MKs和血小板的积累，并且Gata2杂合缺失增强了表达EVI1的祖细胞的Mk谱系倾斜。值得注意的是，inv(3)导向的EVI1表达和Gata2单倍体表达不足共同引发了以MKs和血小板丰富为特征的白血病。小鼠模型的这些血液学特征与在人类3Q AML中观察到的相同。根据这些结果，我们得出结论，Inv(3)驱动的EVI1在HSPC和MKS中的表达与Gata2单倍体不足协同作用，以过多的血小板刺激Mk系倾斜和白血病发生，从而模仿人类AML的一个重要特征。
Chromosomal rearrangements between 3q21 and 3q26 elicit high-risk acute myeloid leukemia (AML), which is often associated with elevated platelet and megakaryocyte (Mk) numbers. The 3q rearrangements reposition a GATA2 enhancer near the EVI1 (or MECOM) locus, which results in both EVI1 overexpression and GATA2 haploinsufficiency. However, the mechanisms explaining how the misexpression of these 2 genes individually contribute to leukemogenesis are unknown. To clarify the characteristics of differentiation defects caused by EVI1 and GATA2 misexpression and to identify the cellular origin of leukemic cells, we generated a system to monitor both inv(3) allele-driven EVI1 and Gata2 expression in 3q-rearranged AML model mice. A cell population in which both EVI1 and Gata2 were highly induced appeared in the bone marrows before the onset of frank leukemia. This population had acquired serial colony-forming potential. Because hematopoietic stem/progenitor cells (HSPCs) and Mks were enriched in this peculiar population, we analyzed the independent EVI1 and GATA2 contributions to HSPC and Mk. We found that inv(3)-driven EVI1 promotes accumulation of Mk-biased and myeloid-biased progenitors, Mks, and platelets, and that Gata2 heterozygous deletion enhanced Mk-lineage skewing of EVI1-expressing progenitors. Notably, inv(3)-directed EVI1 expression and Gata2 haploinsufficient expression cooperatively provoke a leukemia characterized by abundant Mks and platelets. These hematological features of the mouse model phenocopy those observed in human 3q AML. On the basis of these results, we conclude that inv(3)-driven EVI1 expression in HSPCs and Mks collaborates with Gata2 haploinsufficiency to provoke Mk-lineage skewing and leukemogenesis with excessive platelets, thus mimicking an important feature of human AML.