Differential regulation of myeloid leukemias by the bone marrow microenvironment.
Differential regulation of myeloid leukemias by the bone marrow microenvironment.
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作者：
与正常的造血干细胞一样，慢性髓性白血病（CML）和急性髓性白血病（AML）中的白血病干细胞（LSC）被认为存在于骨髓微环境（BMM）的特定生态位中，并且可能是化疗后复发的原因。靶向利基是消除持久性和耐药LSC的新策略。CD44和IL-6先前与LSC生态位有关。转化生长因子(TGF)-β1在骨重塑过程中释放，在CML LSCs的维持中发挥作用，但TGF-β1在BMM中的作用尚未明确。本研究表明，在小鼠移植模型中，成骨细胞特异性激活甲状旁腺激素（PTH）受体对BMM的改变会减弱bcr - abl1诱导的cml样骨髓增生性肿瘤（MPN），但会增强mll - af9诱导的AML，可能是通过TGF-β1增加对相应LSC的相反作用。PTH治疗导致CML样MPN野生型小鼠LSCs减少15倍，并减少免疫缺陷小鼠原代人CML细胞的植入。这些结果表明LSC在慢性和急性髓系白血病中的生态位是不同的，并提示通过PTH调节BMM可能是减少LSC的可行策略，这是治愈CML的先决条件。
Like their normal hematopoietic stem cell counterparts, leukemia stem cells (LSC) in chronic myelogenous leukemia (CML) and acute myeloid leukemia (AML) are presumed to reside in specific niches in the bone marrow microenvironment (BMM), and may be the cause of relapse following chemotherapy. Targeting the niche is a novel strategy to eliminate persistent and drug-resistant LSC. CD44 and IL-6 have been implicated previously in the LSC niche. Transforming growth factor (TGF)-β1 is released during bone remodeling and plays a role in maintenance of CML LSCs, but a role for TGF-β1 from the BMM has not been defined. Here, we show that alteration of the BMM by osteoblastic cell-specific activation of the parathyroid hormone (PTH) receptor attenuates BCR-ABL1-induced CML-like myeloproliferative neoplasia (MPN) but enhances MLL-AF9-induced AML in mouse transplantation models, possibly through opposing effects of increased TGF-β1 on the respective LSC. PTH treatment caused a 15-fold decrease in LSCs in wildtype mice with CML-like MPN, and reduced engraftment of immune deficient mice with primary human CML cells. These results demonstrate that LSC niches in chronic and acute myeloid leukemias are distinct, and suggest that modulation of the BMM by PTH may be a feasible strategy to reduce LSC, a prerequisite for the cure of CML.
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影响因子：
82.9
作者：
通讯作者：
--
影响因子：
64.8
作者：
Naka, Kazuhito;Hoshii, Takayuki;Hirao, Atsushi
通讯作者：
Hirao, Atsushi
DOI：
10.1084/jem.189.9.1399
发表时间：
1999-05-03
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Li S;Ilaria RL Jr;Million RP;Daley GQ;Van Etten RA
通讯作者：
Van Etten RA
影响因子：
20.3
作者：
Heaney, Nicholas B.;Pellicano, Francesca;Holyoake, Tessa L.
通讯作者：
Holyoake, Tessa L.
影响因子：
20.3
作者：
Wang, JCY;Lapidot, T;Dick, JE
通讯作者：
Dick, JE