Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, R4, 1044 West Walnut Street, Indianapolis, IN 46202, USA.
Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, R4, 1044 West Walnut Street, Indianapolis, IN 46202, USA.
Stem Cell Reports. 2020 Jul 14;15(1):95-109. doi: 10.1016/j.stemcr.2020.05.002. Epub 2020 Jun 4.
Studies of patients with acute myeloid leukemia (AML) have led to the identification of mutations that affect different cellular pathways. Some of these have been classified as preleukemic, and a stepwise evolution program whereby cells acquire additional mutations has been proposed in the development of AML. How the timing of acquisition of these mutations and their impact on transformation and the bone marrow (BM) microenvironment occurs has only recently begun to be investigated. We show that constitutive and early loss of the epigenetic regulator, TET2, when combined with constitutive activation of FLT3, results in transformation of chronic myelomonocytic leukemia-like or myeloproliferative neoplasm-like phenotype to AML, which is more pronounced in double-mutant mice relative to mice carrying mutations in single genes. Furthermore, we show that in preleukemic and leukemic mice there are alterations in the BM niche and secreted cytokines, which creates a permissive environment for the growth of mutation-bearing cells relative to normal cells.
对急性髓系白血病 (AML) 患者的研究导致了对影响不同细胞途径的突变的识别。其中一些已被归类为白血病前期，并且已经提出了一个逐步进化的程序，即细胞获得额外的突变，从而导致 AML 的发展。这些突变的获得时间及其对转化和骨髓 (BM) 微环境的影响是如何发生的，最近才开始被研究。我们表明，表观遗传调节剂 TET2 的组成型和早期缺失，与 FLT3 的组成型激活相结合，导致慢性髓单核细胞白血病样或骨髓增生性肿瘤样表型向 AML 的转化，在双突变小鼠中比携带单个基因突变的小鼠更为明显。此外，我们表明，在白血病前期和白血病小鼠中，BM 龛位和分泌的细胞因子发生改变，相对于正常细胞，为携带突变的细胞的生长创造了一个许可环境。
