Lai Courteney K, Moon Yeonsook, Kuchenbauer Florian, Starzcynowski Daniel T, Argiropoulos Bob, Yung Eric, Beer Philip, Schwarzer Adrian, Sharma Amit, Park Gyeongsin, Leung Malina, Lin Grace, Vollett Sarah, Fung Stephen, Eaves Connie J, Karsan Aly, Weng Andrew P, Humphries R Keith, Heuser Michael
Terry Fox Laboratory, BC Cancer Agency Research Centre, Vancouver, BC, Canada; Department of Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
Department of Laboratory Medicine, Medical School of Inha University, Incheon, Korea.
PLoS One. 2014 Nov 17;9(11):e112671. doi: 10.1371/journal.pone.0112671. eCollection 2014.
Extensive molecular profiling of leukemias and preleukemic diseases has revealed that distinct clinical entities, like acute myeloid (AML) and T-lymphoblastic leukemia (T-ALL), share similar pathogenetic mutations. It is not well understood how the cell of origin, accompanying mutations, extracellular signals or structural differences in a mutated gene determine the phenotypic identity of leukemias. We dissected the functional aspects of different protein regions of the MN1 oncogene and their effect on the leukemic phenotype, building on the ability of MN1 to induce leukemia without accompanying mutations. We found that the most C-terminal region of MN1 was required to block myeloid differentiation at an early stage, and deletion of an extended C-terminal region resulted in loss of myeloid identity and cell differentiation along the T-cell lineage in vivo. Megakaryocytic/erythroid lineage differentiation was blocked by the N-terminal region. In addition, the N-terminus was required for proliferation and leukemogenesis in vitro and in vivo through upregulation of HoxA9, HoxA10 and Meis2. Our results provide evidence that a single oncogene can modulate cellular identity of leukemic cells based on its active gene regions. It is therefore likely that different mutations in the same oncogene may impact cell fate decisions and phenotypic appearance of malignant diseases.
对白血病和白血病前期疾病进行的广泛分子分析表明，不同的临床实体，如急性髓系白血病（AML）和T淋巴细胞白血病（T-ALL），具有相似的致病突变。目前尚不清楚起源细胞、伴随的突变、细胞外信号或突变基因的结构差异如何决定白血病的表型特征。基于MN1在无伴随突变的情况下诱导白血病的能力，我们剖析了MN1癌基因不同蛋白区域的功能及其对白血病表型的影响。我们发现，MN1最末端的区域在早期阶段是阻断髓系分化所必需的，而删除一个延伸的末端区域会导致体内髓系特征丧失以及细胞沿T细胞谱系分化。巨核细胞/红系谱系分化被N末端区域阻断。此外，N末端通过上调HoxA9、HoxA10和Meis2在体外和体内的增殖及白血病发生过程中是必需的。我们的结果提供了证据，表明单个癌基因可根据其活性基因区域调节白血病细胞的细胞特征。因此，同一癌基因中的不同突变可能会影响恶性疾病的细胞命运决定和表型表现。
