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.

对急性髓性白血病 (AML) 患者的研究已导致鉴定出影响不同细胞通路的突变。其中一些已被归类为白血病前期，并且在 AML 的发展过程中提出了一种逐步进化程序，通过该程序，细胞获得额外的突变。获取这些突变的时间及其对转化和骨髓 (BM) 微环境的影响最近才开始研究。我们表明，表观遗传调节因子 TET2 的组成型和早期丢失，当与 FLT3 的组成型激活相结合时，会导致慢性粒单核细胞白血病样或骨髓增殖性肿瘤样表型转化为 AML，这在双突变小鼠中更为明显。对携带单基因突变的小鼠。此外，