Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY; Department of Genetics, Albert Einstein College of Medicine, Bronx, NY; Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY.
Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY; Departments of Oncology and Medicine, Albert Einstein College of Medicine-Montefiore Health System, Bronx, NY; Montefiore Einstein Cancer Center, Bronx, NY.
Exp Hematol. 2023 Aug;124:45-55.e2. doi: 10.1016/j.exphem.2023.05.004. Epub 2023 May 22.
TET2 is a member of the Ten-eleven translocation (Tet) family of DNA dioxygenases that regulate gene expression by promoting DNA demethylation (enzymatic activity) and partnering with chromatin regulatory complexes (nonenzymatic functions). TET2 is highly expressed in the hematopoietic lineage, where its molecular functions are the subject of continuous investigations because of the prevalence of TET2 mutations in hematologic malignancies. Previously, we have implicated Tet2 catalytic and noncatalytic functions in the regulation of myeloid and lymphoid lineages, respectively. However, the impact of these functions of Tet2 on hematopoiesis as the bone marrow ages remains unclear. Here, we conducted comparative transplantations and transcriptomic analyses of 3-, 6-, 9-, and 12-month-old Tet2 catalytic mutant (Mut) and knockout (KO) bone marrow. Tet2 Mut bone marrow of all ages exclusively caused hematopoietic disorders of the myeloid lineage. In contrast, young Tet2 KO bone marrow developed both lymphoid and myeloid diseases, whereas older Tet2 KO bone marrow predominantly elicited myeloid disorders with shorter latency than age-matched Tet2 Mut bone marrow. We identified robust gene dysregulation in Tet2 KO Lin cells at 6 months that involved lymphoma and myelodysplastic syndrome and/or leukemia-causing genes, many of which were hypermethylated early in life. There was a shift from lymphoid to myeloid gene deregulation in Tet2 KO Lin cells with age, underpinning the higher incidence of myeloid diseases. These findings expand on the dynamic regulation of bone marrow by Tet2 and show that its catalytic-dependent and -independent roles have distinct impacts on myeloid and lymphoid lineages with age.
TET2 是 Ten-eleven 易位（Tet）家族的 DNA 双加氧酶成员，通过促进 DNA 去甲基化（酶活性）并与染色质调节复合物（非酶活性）合作来调节基因表达。TET2 在造血谱系中高度表达，由于 TET2 突变在血液恶性肿瘤中的普遍性，其分子功能是不断研究的主题。先前，我们已经分别暗示 Tet2 催化和非催化功能在髓系和淋巴谱系的调节中。然而，随着骨髓老化，Tet2 的这些功能对造血的影响仍不清楚。在这里，我们对 3、6、9 和 12 个月大的 Tet2 催化突变（Mut）和敲除（KO）骨髓进行了比较移植和转录组分析。所有年龄段的 Tet2 Mut 骨髓仅导致骨髓髓系造血紊乱。相比之下，年轻的 Tet2 KO 骨髓既发展为淋巴系疾病，也发展为髓系疾病，而较老的 Tet2 KO 骨髓主要引起髓系疾病，潜伏期比同龄的 Tet2 Mut 骨髓短。我们在 6 个月时鉴定了 Tet2 KO Lin 细胞中稳健的基因失调，涉及淋巴瘤和骨髓增生异常综合征和/或白血病致病基因，其中许多基因在生命早期就被高度甲基化。随着年龄的增长，Tet2 KO Lin 细胞中的基因失调从淋巴系向髓系转移，这支持了髓系疾病发病率较高的原因。这些发现扩展了 Tet2 对骨髓的动态调节，并表明其依赖于催化和非依赖于催化的作用对髓系和淋巴系随着年龄的增长具有不同的影响。
