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

SummaryHematopoietic 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 GABPα2β2 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 p210BCR-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.

Graphical AbstractFigure optionsDownload high-quality image (276 K)Download as PowerPoint slideHighlights
► GABPβ1L and GABPβ2 specifically control HSC survival and quiescence
► GABPβ1L and GABPβ2 critically regulate HSC and LSC self-renewal
► Targeting GABPβ1L and GABPβ2 synergizes with imatinib in eradicating CML
► GABP-controlled gene regulatory module is a potential therapeutic target for LSCs