Hematopoietic cell development, T-ALL subgroups and the roles of RUNX1. Different subgroups of T-ALL (TAL/LMO⁺, TLX⁺, and LMO2/LYL⁺) are associated with specific stages of T-cell differentiation. RUNX1 mutations are enriched in ETP ALL. Mutations in the NOTCH1 signaling pathways (NOTCH1 and FBXW7) are enriched in non-ETP T-ALL. In AML cells, mutated RUNX1 fails to bind to DNA or activate transcription.²  This leads to differentiation block via repression of downstream target genes such as CEBPA (top). In non-ETP T-ALL, RUNX1 binds to the MYC and MYB enhancers with the NOTCH1/RBPJ complex and the TAL1 complex, respectively, and activates their expression, thereby promoting T-ALL cell survival (bottom).¹  In this context, RUNX1 serves as an oncogenic factor. In ETP ALL, mutated RUNX1 possibly acts as a tumor suppressor, although detailed mechanisms have not yet been elucidated (middle). CLP, common lymphoid progenitor; DN, double negative (CD4⁻CD8⁻); DP, double positive (CD4⁺CD8⁺); ETP, early T-cell precursor; HSC, hematopoietic stem cell; MPP, multipotent progenitor; SP, single positive (CD4⁺ or CD8⁺).