B-cell identity as a metabolic barrier against malignant transformation.
B-cell identity as a metabolic barrier against malignant transformation.
复制标题
B细胞身份是针对恶性转化的代谢障碍。
DOI：
10.1016/j.exphem.2017.06.004
复制
发表时间：
2017-09
影响因子：
2.6
通讯作者：
Müschen M
中科院分区：
文献类型：
--
作者：
Chan LN;Müschen M
B系和髓系白血病细胞通常由相同的癌基因转化，但具有不同的生物学和临床特征。虽然B系急性淋巴细胞白血病（ALL）细胞的特征是慢性能量缺乏的状态，但髓系白血病细胞显示出丰富的能量储备。有趣的是，禁食已被证明选择性抑制B系ALL的发展，但不是髓系白血病，进一步表明谱系身份可能与造血系统恶性肿瘤的不同代谢状态有关。B淋巴转录因子IKZF 1、EBF 1和PAX 5对于早期B细胞发育和向B细胞身份的定型是必需的。然而，在>80%的人类前B ALL病例中，白血病克隆具有这些转录因子的遗传损伤。这些缺陷的重要性最近才被研究。在这里，我们讨论了意想不到的功能的B淋巴转录程序作为代谢屏障对恶性转化的B细胞前体细胞。B淋巴转录因子的代谢看门人功能可能迫使携带潜在致癌病变的沉默白血病前克隆保持在潜伏状态。此外，该程序还设定了前B ALL对糖皮质激素反应的阈值。最后，肿瘤抑制因子和B淋巴转录因子的代谢功能之间的联系与临床试验中的观察结果相匹配：肥胖和高血糖与前B ALL患者的不良临床结局相关。
B-lineage and myeloid leukemia cells are often transformed by the same oncogenes, but have different biological and clinical characteristics. While B-lineage acute lymphoblastic leukemia (ALL) cells are characterized by a state of chronic energy deficit, myeloid leukemia cells show abundant energy reserve. Interestingly, fasting has been demonstrated to selectively inhibit the development of B-lineage ALL, but not myeloid leukemia, further suggesting that lineage identity may be linked to divergent metabolic states in hematopoietic malignancies. B-lymphoid transcription factors IKZF1, EBF1 and PAX5 are essential for early B cell development and commitment to B cell identity. However, in >80% of human pre-B ALL cases, the leukemic clones harbor genetic lesions of these transcription factors. The significance of these defects has only recently been investigated. Here we discuss the unexpected function of a B-lymphoid transcriptional program as a metabolic barrier against malignant transformation of B cell precursor cells. The metabolic gatekeeper function of B-lymphoid transcription factors may force silent pre-leukemic clones carrying potentially oncogenic lesions to remain in a latent state. In addition, this program sets the threshold for responses to glucocorticoids in pre-B ALL. Finally, the link between tumor suppressor and metabolic functions of B-lymphoid transcription factors is matched by observations in clinical trials: Obesity and hyperglycemia are associated with poor clinical outcome in patients with pre-B ALL.
登录
查看更多内容
DOI：
10.1038/nrc1299
发表时间：
2004-03
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
64.8
作者：
Liu, Yi;Dentin, Renaud;Chen, Danica;Hedrick, Susan;Ravnskjaer, Kim;Schenk, Simon;Milne, Jill;Meyers, David J.;Cole, Phil;Yates, John, III;Olefsky, Jerrold;Guarente, Leonard;Montminy, Marc
通讯作者：
Montminy, Marc
影响因子：
158.5
作者：
Druker, Brian J.;Guilhot, Francois;Larson, Richard A.
通讯作者：
Larson, Richard A.
影响因子：
4.8
作者：
Fretz, Jackie A.;Nelson, Tracy;Horowitz, Mark C.
通讯作者：
Horowitz, Mark C.
影响因子：
4.8
作者：
Gruver-Yates, Amanda L.;Quinn, Matthew A.;Cidlowski, John A.
通讯作者：
Cidlowski, John A.