Expression of constitutively activated human c-Kit in Myb transformed early myeloid cells leads to factor independence, histiocytic differentiation, and tumorigenicity.
Expression of constitutively activated human c-Kit in Myb transformed early myeloid cells leads to factor independence, histiocytic differentiation, and tumorigenicity.
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Myb 转化的早期骨髓细胞中组成型激活的人 c-Kit 的表达导致因子独立性、组织细胞分化和致瘤性。
DOI：
10.1182/blood.v90.11.4539
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发表时间：
1997
期刊：
影响因子：
20.3
通讯作者：
L. Ashman
中科院分区：
文献类型：
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作者：
P. Ferrao;T. Gonda;L. Ashman
将编码野生型（WT）人受体酪氨酸激酶c-Kit和组成型激活突变体V816 Kit的cDNA导入已用激活的Myb转化的依赖粒细胞-巨噬细胞集落刺激因子（GM-CSF）的早期小鼠造血细胞中。WTKit细胞能够在Kit的人配体干细胞因子（SCF）存在下生长，但与GM-CSF中的亲本细胞相比，在SCF或GM-CSF中显示出降低的生长和克隆形成潜力。相比之下，V816 Kit细胞在没有因子的情况下以比GM-CSF中的亲本细胞更高的速率生长，并且显示出增加的克隆形成性。在液体培养中的生长特性的剖析表明，在适当的因素的存在下，不同的群体具有相似的增殖率，但V816试剂盒大大增加了细胞存活与WTKit或亲本细胞相比。这表明SCF激活的WTKit和V816 Kit转导的信号是不同的。此外，WTKit和V816 Kit表达细胞均不同于亲本细胞的早期髓系祖细胞表型，并产生少量表达巨噬细胞（α-乙酸萘酯）酯酶和嗜中性粒细胞（naphtol-AS-D-氯乙酸酯酶）酯酶的大至巨贴壁细胞，具有高度吞噬作用，表型类似于组织细胞。因此，由SCF和V816 Kit激活的WTKit能够诱导一定比例的Myb转化的髓样细胞分化。与亲本和WTKit表达细胞不同，因子非依赖性V816 Kit细胞显示在同基因小鼠中在不同分化阶段产生高度有丝分裂的侵袭性细胞的肿瘤。这些结果表明，组成性激活的Kit可以促进分化的髓系肿瘤的发展，其致癌作用并不局限于谱系（肥大细胞和B细胞急性淋巴细胞白血病），这是以前报道过的。此外，培养物和肿瘤中的混合细胞群在表型上类似于来自具有组织细胞分化的单核细胞白血病（急性髓性白血病-M5 c）（一种新提出的髓性白血病亚型）患者的白血病细胞。
The cDNAs encoding wild type (WT) human receptor tyrosine kinase c-Kit and a constitutively activated mutant, V816Kit, were introduced into granulocyte-macrophage colony-stimulating factor (GM-CSF )-dependent early murine hemopoietic cells, which had been transformed with activated Myb. WTKit cells were able to grow in the presence of the human ligand for Kit, stem cell factor (SCF ), but displayed reduced growth and clonogenic potential in either SCF or GM-CSF compared with the parental cells in GM-CSF. In contrast, V816Kit cells grew without factor at a higher rate than the parental cells in GM-CSF and displayed increased clonogenicity. Dissection of the growth characteristics in liquid culture showed that in the presence of appropriate factors, the different populations had similar proliferation rates, but that V816Kit profoundly increased cell survival compared with WTKit or parental cells. This suggests that the signals transduced by WTKit activated with SCF, and by V816Kit, were not identical. Also, WTKit and V816Kit-expressing cells both varied from the early myeloid progenitor phenotype of the parental cells and gave rise to a small number of large to giant adherent cells that expressed macrophage (alpha-naphthyl acetate) esterase and neutrophil (naphtol-AS-D-chloroacetate) esterase, were highly phagocytic and phenotypically resembled histiocytes. Thus, WTKit activated by SCF and V816Kit were able to induce differentiation in a proportion of Myb-transformed myeloid cells. The factor independent V816Kit cells, unlike the parental and WTKit expressing cells, were shown to produce tumors of highly mitotic, invasive cells at various stages of differentiation in syngeneic mice. These results imply that constitutively activated Kit can promote the development of differentiated myeloid tumors and that its oncogenic effects are not restricted to lineages (mast cell and B-cell acute lymphoblastic leukemia), which have been reported previously. Furthermore, the mixed populations of cells in culture and in the tumors phenotypically resembled the leukemic cells from patients with monocytic leukemia with histiocytic differentiation (acute myeloid leukemia-M5c), a newly proposed subtype of myeloid leukemia.
DOI：
--
发表时间：
1991-12
期刊：
Cancer cells
影响因子：
--
作者：
H. Broxmeyer;R. Maze;Keisuke Miyazawa;C. Carow;Paul C. Hendrie;S. Cooper;G. Hangoc;Saroj Vadhan-Raj;Li Lu
通讯作者：
H. Broxmeyer;R. Maze;Keisuke Miyazawa;C. Carow;Paul C. Hendrie;S. Cooper;G. Hangoc;Saroj Vadhan-Raj;Li Lu
影响因子：
2.7
作者：
BUTTERFIELD, JH;WEILER, D;GLEICH, GJ
通讯作者：
GLEICH, GJ