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Elp1_deficency_during_early_myeloid_differentiation

ABSTRACT: The replacement of microglia with myeloid cells derived from transplanted bone marrow represents a promising cell therapeutic concept for different neurological disorders. Previous studies have primarily been based on freshly harvested grafts, permitting only limited control over cells prior to transplantation. Here we demonstrate the ability of in vitro expanded hematopoietic stem and progenitor cells (cHSPCs) to engraft in the myeloid niche of the brain, and effectively replace endogenous microglia both in vivo and in vitro. Utilizing genetic editing of cHSPCs, we identify elongator acetyltransferase complex subunit 1 (Elp1; also known as Ikbkap; encoding for the protein IKAP) as an essential gene for the generation of cHSPC-derived myeloid cells (HDMCs). In accordance with its role as a subunit of the Elongator complex, loss of Elp1 in early-stage HDMCs led to upregulation of a gene module associated with the unfolded protein response.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture

SUBMITTER: Marius Mader

LAB HEAD: Marius Wernig

PROVIDER: PXD049985 | Pride | 2026-07-18

REPOSITORIES: Pride

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			Action	DRS
	20221202_Wernig_MMader_11990_B_1_no.raw	Raw
	20221202_Wernig_MMader_11990_B_1_pos.raw	Raw
	20221202_Wernig_MMader_11990_B_2_no.raw	Raw
	20221202_Wernig_MMader_11990_B_2_pos.raw	Raw
	20221202_Wernig_MMader_11990_B_3_no.raw	Raw

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Project description:Cancer genomics has illuminated a wide spectrum of genes and core molecular processes contributing to human malignancy. Still, the genetic and molecular basis of many cancers remains only partially explained. Genetic predisposition accounts for 5-10% of cancer diagnoses and genetic events cooperating with known somatic driver events are poorly understood. Analyzing established cancer predisposition genes in medulloblastoma (MB), a malignant childhood brain tumor, we recently identified pathogenic germline variants that account for 5% of all MB patients. Here, by extending our previous analysis to include all protein-coding genes, we discovered and replicated rare germline loss-of-function (LoF) variants across Elongator Complex Protein 1 (ELP1) on 9q31.3 in 15% of pediatric MBSHH cases, thus implicating ELP1 as the most common MB predisposition gene and increasing genetic predisposition to 40% for pediatric MBSHH. Inheritance was verified based on parent-offspring and pedigree analysis, which identified two families with a history of pediatric MB. ELP1-associated MBs were restricted to the molecular SHH subtype and were characterized by universal biallelic inactivation of ELP1 due to somatic loss of chromosome 9q. The majority of ELP1-associated MBs exhibited co-occurring somatic PTCH1 (9q22.32) alterations, suggesting that ELP1-deficiency predisposes to tumor development in combination with constitutive activation of SHH signaling. ELP1 is an essential subunit of the evolutionary conserved Elongator complex, whose primary function is to enable efficient translational elongation through tRNAs modifications at the wobble (U34) position. Biochemical, transcriptional, and proteomic analyses revealed that ELP1-associated MBSHH are characterized by a destabilized core Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response (UPR), consistent with deregulation of protein homeostasis due to Elongator-deficiency in model systems. Our findings suggest that genetic predisposition to proteome instability is a previously underappreciated determinant in the pathogenesis of pediatric brain cancer. These results provide strong rationale for further investigating the role of protein homeostasis in other pediatric and adult cancer types and potential opportunities for novel therapeutic interference.

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Elp1_deficency_during_early_myeloid_differentiation

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