在应激造血恢复过程中，MCL-1与PUMA之间的拮抗作用决定了干细胞/祖细胞的存活。
Antagonism between MCL-1 and PUMA governs stem/progenitor cell survival during hematopoietic recovery from stress.
作者信息
Delbridge Alex R D, Opferman Joseph T, Grabow Stephanie, Strasser Andreas
机构信息
Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; Department of Medical Biology, University of Melbourne, Melbourne, Australia; and.
Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN.
出版信息
Blood. 2015 May 21;125(21):3273-80. doi: 10.1182/blood-2015-01-621250. Epub 2015 Apr 6.
Understanding the critical factors that govern recovery of the hematopoietic system from stress, such as during anticancer therapy and bone marrow transplantation, is of clinical significance. We investigated the importance of the prosurvival proteins myeloid cell leukemia-1 (MCL-1) and B-cell lymphoma-extra large (BCL-XL) in stem/progenitor cell survival and fitness during hematopoietic recovery from stress. Loss of a single Mcl-1 allele, which reduced MCL-1 protein levels, severely compromised hematopoietic recovery from myeloablative challenge and following bone marrow transplantation, whereas BCL-XL was dispensable in both contexts. We identified inhibition of proapoptotic p53 upregulated modulator of apoptosis (PUMA) as the key role of MCL-1 in both settings, with Mcl-1(+/-);Puma(-/-) mice completely protected from the deleterious effects of loss of 1 Mcl-1 allele. These results reveal the molecular mechanisms that govern cell survival during hematopoietic recovery from stress.
了解在诸如抗癌治疗和骨髓移植等应激过程中，调控造血系统恢复的关键因素具有临床意义。我们研究了促生存蛋白髓样细胞白血病-1（MCL-1）和B细胞淋巴瘤-超大蛋白（BCL-XL）在应激造血恢复过程中对干细胞/祖细胞存活和健康状况的重要性。单个Mcl-1等位基因的缺失会降低MCL-1蛋白水平，严重损害从清髓性攻击以及骨髓移植后的造血恢复，而在这两种情况下BCL-XL都是可有可无的。我们确定抑制促凋亡的p53上调凋亡调节因子（PUMA）是MCL-1在这两种情况下的关键作用，Mcl-1(+/-);Puma(-/-)小鼠完全免受1个Mcl-1等位基因缺失的有害影响。这些结果揭示了在应激造血恢复过程中调控细胞存活的分子机制。
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