Alterations of H3K9me2 in hematopoietic stem cells: implications for aging and myeloid leukemogenesis

随着年龄的增长，HSC显示出关键的功能下降，这是由全局和局部DNA和组蛋白甲基化以及组蛋白乙酰化的变化引起的。这种表观遗传漂变可能导致DNA转录异常或损害DNA复制和修复，并可能通过这种方式促进癌症的发展。例如，AML主要是老年患者的疾病，其起源于造血祖细胞/干细胞，并显著影响表观基因组。白血病干细胞（LSC）的表观基因组维持在成髓细胞中，并影响疾病的侵袭性和结果。最近的研究表明，组蛋白去甲基化酶JMJD 1C作为RUNX 1 RUNX 1 T1（以前称为AML 1 ETO）的共激活剂发挥作用，并且通过维持低水平的H3 K9 me 2特异性，在AML中对其转录程序是必需的，这进一步暗示了HSC和AML的表观遗传学变化之间的直接联系。H3 K9 me 2虽然还没有研究到目前为止，在HSC和老化和白血病转化。从我的实验室的初步数据表明，H3 K9 me 2在静止的小鼠HSC的细胞核和小鼠HSC分裂后的子细胞中的分布在老化时明显改变。用卡辛处理老年HSC恢复了H3 K9 me 2在老年HSC和干细胞分裂后的子细胞中的年轻分布。我假设，HSC老化时H3 K9 me 2沉积的改变有助于HSC向AML干细胞的老化相关转变，并通过卡辛治疗靶向H3 K9 me 2分布，和/或因此，本研究的目的是（1）确定小鼠HSC老化后H3 K9 me 2分布/水平的改变程度，并研究老化是否会影响H3 K9 me 2的分布/水平。通过卡辛处理或通过抑制JMJD 1C活性将相关变化恢复到年轻水平;（2）研究人HSC是否存在，类似于鼠HSC，在老化时H3 K9 me 2分布发生变化;（3）确定AML干细胞是否存在改变的H3 K9 me 2分布，并研究靶向鼠LSC中H3 K9 me 2的水平和/或分布是否改变白血病的起始和进展。

Upon aging HSCs show a critical functional decline that is paralleled by changes in global and local DNA and histone methylation as well as histone acetylation. This epigenetic drift might contribute to aberrant DNA transcription or impair DNA replication and repair, and might by this means contribute to the development of cancer. For instance, AML is predominantly a disease of older patients that originates in hematopoietic progenitor/stem cells and affects substantially the epigenome. The epigenome of leukemia stem cells (LSCs) is maintained in the myeloblast and influence aggressiveness and outcome of the disease. Recently it was shown that the histone demethylase JMJD1C functions as a coactivator for RUNX1RUNX1T1 (formerly AML1ETO) and is required for its transcriptional program in AML by maintaining low levels specifically of H3K9me2, further implying a direct connection between changes in epigenetics of HSCs and AML. H3K9me2 though has not been studied so far in HSCs and upon aging and leukemic transformation. Preliminary data from my laboratory indicate that the distribution of H3K9me2 in the nucleus of quiescent murine HSCs and in daughter cells upon murine HSC division is distinctly altered upon aging. Treatment of aged HSCs with CASIN restored a youthful distribution of H3K9me2 in aged HSCs and in daughter cells upon stem cell division.Based on my preliminary data and on data recently published by others, I hypothesize that alterations in H3K9me2 deposition upon aging of HSCs contribute to the aging-associated transition of HSCs to AML stem cells and targeting H3K9me2 distribution via CASIN treatment and/or H3K9me2 levels via inhibition of the histone demethylase JMJD1C could represent an approach to decrease aggressiveness of LSCs in AML.Therefore the current proposal aims are (1) to determine the extent of the alterations in H3K9me2 distribution/levels upon aging of murine HSCs and investigate whether the aging-associated changes are reverted to a youthful level by CASIN treatment of by inhibition of JMJD1C activity; (2) to investigate whether human HSCs present, similar to murine HSCs, with changes in H3K9me2 distribution upon aging; (3) to determine whether AML stem cells present with altered H3K9me2 distribution and investigate whether targeting the level and/or the distribution of H3K9me2 in murine LSCs alters leukemia initiation and progression.