Deleting Mcl-1 in mast cells: getting 2 birds with 1 stone.

REFERENCES 1. Hegde S, Kaushal N, Ravindra KC, et al. delta12-pros-taglandin J3, an omega-3 fatty acid-derived metabolite, selectively ablates leukemia stem cells in mice. 2. Mozaffarian D, Lemaitre RN, King IB, et al. Circulating long-chain omega-3 fatty acids and incidence of congestive heart failure in older adults: the cardiovascular health study: a cohort study. polyunsaturated fatty acids and colon cancer prevention. of agents that eradicate leukemia stem cells using an in silico screen of public gene expression data. Targeting multiple kinase pathways in leukemic progenitors and stem cells is essential for improved treatment of Phϩ leukemia in mice.1 is a putative oncogene in virally induced murine erythroleuke-mias. In this issue of Blood, Lilla and colleagues report that Mcl-1 (myeloid cell leukemia sequence 1), an intracellular antiapoptotic factor in a multiple hematopoietic lin-eage cells, plays a crucial role in regulating survival of both mast cells and baso-phils. 1 M cl-1 belongs to the bcl-2 family proteins and has been considered a master regulator of cell survival. Earlier studies that used Mcl-1-floxed mice that express Cre recombi-nase under different cell type–specific promoters demonstrated that Mcl-1 plays an essential role in maintaining survival of multiple cell types including lymphocytes, neutrophils, hepatocytes, and neurons. 2-4 As both mast cells and basophils are also known to express Mcl-1, the authors directly investigated whether Mcl-1 exerts antiapoptotic functions in these cells by selectively deleting Mcl-1 by expressing Cre recombinase under the promoter of carboxypeptidase A3 (CPA3; referred to as Cpa3-Cre;Mcl-1 fl/fl mice hereafter), a gene highly expressed in mast cells and basophils. First, they confirmed CPA3-induced Cre recombinase expression in various cell types. As expected, high levels of Cre expression was observed in peritoneal mast cells. Conversely, the level of CPA3-induced Cre expression in basophils was substantially lower than that of mast cells. Moreover, the level of Cre expression in other granulocytes such as eosinophils and neutrophils was not different from that in basophils. When Cpa3-Cre; Mcl-1 fl/fl mice were analyzed, mast cell numbers were dramatically reduced in all tested tissues. The authors also found that the numbers of basophils in these mice were substantially diminished, while other granulo-cytes including eosinophils and neutrophils, despite the similar CPA3-induced Cre expression , were not affected by the lack of Mcl-1. Therefore, a selective defect in the survival of both mast cells and basophils is achieved in the Cpa3-Cre;Mcl-1 fl/fl mice. Using the Cpa3-Cre;Mcl-1 fl/fl mice, the authors then …