HDGF-related protein 2 (HRP-2) is a member of the Hepatoma-Derived Growth Factor-related protein family that harbors the structured PWWP and Integrase Binding Domain, known to associate with methylated histone tails or cellular and viral proteins, respectively. Interestingly, HRP-2 is a paralog of Lens Epithelium Derived Growth Factor p75 (LEDGF/p75), which is essential for MLL-rearranged (MLL-r) leukemia but dispensable for hematopoiesis. Sequel to these findings, we investigated the role of HRP-2 in hematopoiesis and MLL-r leukemia. Protein interactions were investigated by co-immunoprecipitation and validated using recombinant proteins in NMR. A systemic knockout mouse model was used to study normal hematopoiesis and MLL-ENL transformation upon the different HRP-2 genotypes. The role of HRP-2 in MLL-r and other leukemic, human cell lines was evaluated by lentiviral-mediated miRNA targeting HRP-2. We demonstrate that MLL and HRP-2 interact through a conserved interface, although this interaction proved less dependent on menin than the MLL-LEDGF/p75 interaction. The systemic HRP-2 knockout mice only revealed an increase in neutrophils in the peripheral blood, whereas the depletion of HRP-2 in leukemic cell lines and transformed primary murine cells resulted in reduced colony formation independently of MLL-rearrangements. In contrast, primary murine HRP-2 knockout cells were efficiently transformed by the MLL-ENL fusion, indicating that HRP-2, unlike LEDGF/p75, is dispensable for the transformation of MLL-ENL leukemogenesis but important for leukemic cell survival.

中文翻译：

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与它的 Paralog LEDGF/p75 不同，HRP-2 对于 MLL-R 白血病发生是可有可无的，但对白血病细胞存活很重要

HDGF 相关蛋白 2 (HRP-2) 是肝癌衍生的生长因子相关蛋白家族的成员，它包含结构化的 PWWP 和整合酶结合域，已知分别与甲基化组蛋白尾部或细胞和病毒蛋白相关联。有趣的是，HRP-2 是晶状体上皮衍生生长因子 p75 (LEDGF/p75) 的旁系同源物，它对MLL重排 ( MLL -r) 白血病至关重要，但对造血却非必需。继这些发现后，我们研究了 HRP-2 在造血和MLL 中的作用-r 白血病。通过免疫共沉淀研究蛋白质相互作用，并在 NMR 中使用重组蛋白质进行验证。系统敲除小鼠模型用于研究不同 HRP-2 基因型的正常造血和 MLL-ENL 转化。HRP-2 在MLL -r 和其他白血病、人类细胞系中的作用通过靶向 HRP-2 的慢病毒介导的 miRNA 进行评估。我们证明了 MLL 和 HRP-2 通过一个保守的界面相互作用，尽管这种相互作用被证明比 MLL-LEDGF/p75 相互作用对menin 的依赖性更小。全身性 HRP-2 敲除小鼠仅显示外周血中性粒细胞增加，而白血病细胞系和转化的原代鼠细胞中 HRP-2 的消耗导致集落形成减少，与MLL无关- 重新安排。相比之下，原代小鼠 HRP-2 敲除细胞被 MLL-ENL 融合有效转化，表明 HRP-2 与 LEDGF/p75 不同，对于 MLL-ENL 白血病发生的转化是不必要的，但对白血病细胞的存活很重要。