Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Cell Stem Cell. 2012 Aug 3;11(2):207-19. doi: 10.1016/j.stem.2012.05.021.
Hematopoietic stem cells (HSCs) and leukemic stem cells (LSCs) are both capable of self-renewal, with HSCs sustaining multiple blood lineage differentiation and LSCs indefinitely propagating leukemia. The GABP complex, consisting of DNA binding GABPα subunit and transactivation GABPβ subunit, critically regulates HSC multipotency and self-renewal via controlling an essential gene regulatory module. Two GABPβ isoforms, GABPβ1L and GABPβ2, contribute to assembly of GABPα(2)β(2) tetramer. We demonstrate that GABPβ1L/β2 deficiency specifically impairs HSC quiescence and survival, with little impact on cell cycle or apoptosis in differentiated blood cells. The HSC-specific effect is mechanistically ascribed to perturbed integrity of the GABP-controlled gene regulatory module in HSCs. Targeting GABPβ1L/β2 also impairs LSC self-renewal in p210(BCR-ABL)-induced chronic myelogenous leukemia (CML) and exhibits synergistic effects with tyrosine kinase inhibitor imatinib therapy in inhibiting CML propagation. These findings identify the tetramer-forming GABPβ isoforms as specific HSC regulators and potential therapeutic targets in treating LSC-based hematological malignancy.
造血干细胞（HSCs）和白血病干细胞（LSCs）都具有自我更新的能力，HSCs 维持多种血液谱系分化，而 LSCs 则无限期地增殖白血病。GABP 复合物由 DNA 结合 GABPα 亚基和转录激活 GABPβ 亚基组成，通过控制一个必需的基因调控模块，对 HSC 多能性和自我更新起着至关重要的调节作用。两种 GABPβ 同工型 GABPβ1L 和 GABPβ2 有助于 GABPα(2)β(2)四聚体的组装。我们证明 GABPβ1L/β2 缺陷特异性损害 HSC 静止和存活，而对分化血细胞的细胞周期或凋亡影响很小。HSC 特异性效应归因于 GABP 调控的基因调控模块在 HSCs 中的完整性受到干扰。靶向 GABPβ1L/β2 还会损害 p210(BCR-ABL)诱导的慢性髓系白血病（CML）中的 LSC 自我更新，并与酪氨酸激酶抑制剂伊马替尼治疗协同抑制 CML 的增殖。这些发现确定了形成四聚体的 GABPβ 同工型是治疗基于 LSC 的血液恶性肿瘤的特定 HSC 调节剂和潜在治疗靶点。
