The transcription factor RUNX1 is a master regulator of hematopoiesis and is frequently mutated in myeloid and lymphoid malignancies. RUNX1 mutations frequently disrupt DNA binding and result in loss of RUNX1 function. However, it is not clearly understood how other RUNX1 mutations contribute to disease development. Here, we characterize pathogenic RUNX1 mutations that do not directly affect DNA binding. Our analysis of patient datasets revealed that mutations within the C-terminus frequently occur in leukemia. Further assessment uncovered that most of these mutations consist of nonsense and frameshift mutations and are predicted to escape nonsense mediated decay. Therefore, this class of mutation is projected to produce DNA-binding proteins that contribute to pathogenesis in a distinct manner. To model this, we introduced the RUNX1R320* mutation into the endogenous gene locus and demonstrated the production of RUNX1R320* protein. Expression of RUNX1R320* resulted in the dysregulation of RUNX1 controlled processes such as megakaryocytic differentiation through a transcriptional signature different from RUNX1 depletion. To understand the underlying mechanisms, we utilized Global RNA Interactions with DNA by deep sequencing (GRID-seq) to examine enhancer-promoter connections. We identified wide-spread alteration of enhancer-promoter networks within RUNX1 mutant cells. Additionally, we uncovered a novel cooperation between RUNX1R320* and FOXK2 at the MYC super enhancer locus, significantly upregulating MYC transcription and signaling pathways. Together, our study demonstrates that RUNX1 mutations outside the DNA binding domain frequently escape nonsense mediated decay, producing protein products that act in concert with additional cofactors to dysregulate hematopoiesis through mechanisms distinct from RUNX1 depletion.