Targeting Tetramer-Forming GABPβ Isoforms Impairs Self-Renewal of Hematopoietic and Leukemic Stem Cells

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 GABP alpha subunit and transactivation GABP beta subunit, critically regulates HSC multipotency and self-renewal via controlling an essential gene regulatory module. Two GABP beta isoforms, GABP beta 1L and GABP beta 2, contribute to assembly of GABP alpha(2)beta(2) tetramer. We demonstrate that GABP beta 1L/beta 2 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 GABP beta 1L/beta 2 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 GABP beta isoforms as specific HSC regulators and potential therapeutic targets in treating LSC-based hematological malignancy.