KLF4/MLL3 axis Drives NRBP2 Transcription to Eliminate Acute Myeloid Leukemia Cells

Acute myeloid leukemia (AML) is a heterogeneous malignancy rooted in hematopoietic stem cell dysregulation. Despite therapeutic advances, clinical outcomes remain unsatisfactory. Here, we identify KLF4, a zinc finger transcription factor with previously reported context-dependent roles in hematologic malignancies, as a negative regulator of AML proliferation. Mechanistically, KLF4 interacts with the MLL3 histone methyltransferase complex, comprising MLL3, WDR5, RBBP5 and ASH2L, through its zinc finger (ZnF) and transrepression domain (TRD) domains, and actives transcription of the tumor suppressor gene NRBP2. Furthermore, integrated transcriptional profiling revealed TNIK as a convergent effector of the KLF4–NRBP2 tumor-suppressive circuit in acute myeloid leukemia. Pharmacological blockade of TNIK with the selective small-molecule inhibitor TNIK-IN-1 selectively impaired leukemic cell proliferation while sparing normal haematopoiesis. Consequently, our findings reveal a previously unrecognized KLF4–MLL3–NRBP2 transcriptional axis and its pharmacological re-engagement with TNIK-IN-1 establishes this axis as a directly druggable vulnerability in AML.