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Targeting Menin in T-Lineage Acute Lymphoblastic Leukemia

ABSTRACT: The efficacy of menin inhibition was evaluated in 14 primary T-ALL samples with diverse genetic backgrounds using ziftomenib. Sensitivity was not correlated with HOXA expression or KMT2A rearrangements, and in vivo treatment significantly reduced tumor burden in xenograft models without notable toxicity. Transcriptomic and proteomic analyses confirmed on-target activity, including downregulation of menin targets and activation of differentiation pathways. Phosphoproteomic profiling identified phospho-MEF2C (S222) as a key marker of sensitivity, regulated by CDK and MAPK signaling. Combination treatment with ziftomenib and CDK1/2 or ERK1/2 inhibitors showed synergistic effects, suggesting a mechanistic link between menin inhibition and p-MEF2C–driven T-ALL vulnerability.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Leukocyte, Blood

DISEASE(S): Acute Leukemia

SUBMITTER: Diren Arda Karaoglu

LAB HEAD: Caner Saygin

PROVIDER: PXD065185 | Pride | 2026-03-05

REPOSITORIES: Pride

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			Action	DRS
	T-ALL3_treated_r1.raw	Raw
	T-ALL3_treated_r2.raw	Raw
	T-ALL3_untreated_r1.raw	Raw
	T-ALL3_untreated_r2.raw	Raw
	T-ALL8_treated_r1.raw	Raw

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Targeting Menin in T-Lineage Acute Lymphoblastic Leukemia [MEF2CKD]

Project description:The efficacy of menin inhibition was evaluated in 14 primary T-ALL samples with diverse genetic backgrounds using ziftomenib. Sensitivity was not correlated with HOXA expression or KMT2A rearrangements, and in vivo treatment significantly reduced tumor burden in xenograft models without notable toxicity. Transcriptomic and proteomic analyses confirmed on-target activity, including downregulation of menin targets and activation of differentiation pathways. Phosphoproteomic profiling identified phospho-MEF2C (S222) as a key marker of sensitivity, regulated by CDK and MAPK signaling. Combination treatment with ziftomenib and CDK1/2 or ERK1/2 inhibitors showed synergistic effects, suggesting a mechanistic link between menin inhibition and p-MEF2C–driven T-ALL vulnerability.

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Multi-omics analysis of MEN1 missense mutations identifies disruption of menin-MLL and menin-JunD interactions as critical requirements for molecular pathogenicity

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