IKAROS and MENIN coordinate therapeutically actionable leukemogenic gene expression in MLL-r acute myeloid leukemia

Abstract

Acute myeloid leukaemia (AML) remains difficult to treat and requires new therapeutic approaches. Potent inhibitors of the chromatin-associated protein MENIN have recently entered human clinical trials, opening new therapeutic opportunities for some genetic subtypes of this disease. Using genome-scale functional genetic screens we identified IKZF1 /IKAROS as an essential transcription factor in MLL1-rearranged ( MLL - r ) AML that maintains leukaemogenic gene expression while also repressing pathways for tumour suppression, immune regulation, and cellular differentiation. Furthermore, IKAROS displays an unexpected functional cooperativity and extensive chromatin co-occupancy with MLL1/MENIN and MEIS1 and an extensive hematopoietic transcriptional complex involving HOXA10, MEIS1 and IKAROS. This dependency could be therapeutically exploited by inducing IKAROS protein degradation with immunomodulatory imide drugs (IMiDs). Finally, we demonstrate that combined IKAROS degradation and MENIN inhibition effectively disrupts leukaemogenic transcriptional networks resulting in synergistic killing of leukaemia cells and providing a paradigm for improved drug-targeting of transcription, and an opportunity for rapid clinical translation.

Activity of menin inhibitor ziftomenib (KO-539) as monotherapy or in combinations against AML cells with MLL1 rearrangement or mutant NPM1

“…S3J and S3K) [10]. We also confirmed that IKAROS (encoded by IKZF1) is a dependency in KMT2A (MLL1)rearranged (MLL1-r) and mtNPM1-expressing AML cells [15], by demonstrating that CRISPR knockout of IKZF1 significantly increased sensitivity of OCI-AML3 cells to ziftomenib (Supplementary Figs. S4A and S4B).…”

Identification of IKZF1 genetic mutations as new molecular subtypes in acute myeloid leukaemia

“…Among them, IKZF1 N159S was a recurrent hotspot mutation, which closely clustered in a subset of patients with myelodysplasia‐related mutations and upregulated gene expression of the HOXA / B family genes 14 . Notably, immunomodulatory drugs inducing IKAROS protein degradation showed potential therapeutic efficiency in the HOXA ‐related AML, which suggests the emerging synergistic role of IKAROS in high‐risk AML 27 …”

“…14 Notably, immunomodulatory drugs inducing IKAROS protein degradation showed potential therapeutic efficiency in the HOXA-related AML, which suggests the emerging synergistic role of IKAROS in high-risk AML. 27 To date, a few critical issues remain to be addressed to further explore the pathogenesis and improve the prognosis of AML patients with IKZF1 mutations. Firstly, genetic alterations of IKZF1 are common and widely reported in B-ALL, however, the genomic landscape, molecular classification and clinical significance are scarcely investigated in a large AML cohort.…”

The future of HOXA-expressing leukemias: Menin inhibitor response and resistance

“…Similarly, combined Menin- and FLT3 inhibition had synergistic effects in KMT2A -rearranged and NPM1c leukemia [57,58]. Apart from that, combined degradation of the transcription factor Ikaros (IKZF) by mezigdomide treatment and Menin inhibition has shown synergistic effects in preclinical AML models [59,60 ▪ ].…”