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KLF4/MLL3 Complex axis Drives NRBP2 Transcription to Eliminate Acute Myeloid Leukemia Cells [Cut & Tag]

ABSTRACT: 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 (ZnF) 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. KLF4 engages the catalytic subunit MLL3 and the allosteric regulator ASH2L through its ZnF and transrepression (TRD) domains, thereby activating transcription of the tumor suppressor gene NRBP2. Furthermore, integrated transcriptional analysis 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 hematopoiesis. Consequently, our findings reveal a previously unrecognized KLF4–MLL3 complex–NRBP2 transcriptional axis that suppresses AML survival through TNIK, highlighting a potential therapeutic strategy for AML.

ORGANISM(S): Homo sapiens

PROVIDER: GSE328080 | GEO | 2026/08/15

REPOSITORIES: GEO

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

Project description: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 (ZnF) 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. KLF4 engages the catalytic subunit MLL3 and the allosteric regulator ASH2L through its ZnF and transrepression (TRD) domains, thereby activating transcription of the tumor suppressor gene NRBP2. Furthermore, integrated transcriptional analysis 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 hematopoiesis. Consequently, our findings reveal a previously unrecognized KLF4–MLL3 complex–NRBP2 transcriptional axis that suppresses AML survival through TNIK, highlighting a potential therapeutic strategy for AML.

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

| PRJNA1312010 | ENA