Blocking UBE2N abrogates oncogenic immune signaling in acute myeloid leukemia

Barreyro, Laura; Sampson, Avery; Ishikawa, Chiharu; Hueneman, Kathleen; Choi, Kwangmin; Pujato, Mario; Wyder, Michael; Haffey, Wendy D.; O’Brien, Eric; Wunderlich, Mark; Ramesh, Vighnesh; Gagliani, Ellen K.; Meydan, Cem; Neelamraju, Yaseswini; Bolanos, Lyndsey; Christie, Susanne; Smith, Molly A.; Niederkorn, Madeline; Muto, Tomoya; Kesari, Santosh; Garrett-Bakelman, Francine E.; Bartholdy, Boris; Will, Britta; Weirauch, Matthew T.; Mulloy, James C.; Gul, Zartash; Medlin, Stephen; Kovall, Rhett A.; Melnick, Ari; Perentesis, John P.; Greis, Kenneth D.; Nurmemmedov, Elmar; Seibel, William; Starczynowski, Daniel T.

doi:10.1126/scitranslmed.abb7695

Cited by 16 publications

(16 citation statements)

References 104 publications

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“…In prior studies, we found that UBE2N is required for leukemic cell function in vitro and in vivo by maintaining oncogenic immune signaling states. 58 UBE2N (Ubc13) is a ubiquitin-conjugating enzyme implicated in the regulation of TRAF6, an E3 ubiquitin ligase and effector of the TLR/IL1R signaling pathway. 59 Using small-molecule inhibitors identified in in silico structure-based and cellular-based screens, we revealed the therapeutic efficacy of interfering with UBE2N function by blocking of ubiquitination of innate immune- and inflammatory-related substrates in human AML cells.…”

Section: Discussionmentioning

confidence: 99%

Dysregulated innate immune signaling cooperates with RUNX1 mutations to transform an MDS-like disease to AML

Barreyro,

Sampson,

Hueneman

et al. 2024

iScience

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Section: Discussionmentioning

confidence: 99%

Dysregulated innate immune signaling cooperates with RUNX1 mutations to transform an MDS-like disease to AML

Barreyro,

Sampson,

Hueneman

et al. 2024

iScience

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“…Several attempts are being pursued to restore normal innate immune signaling in MDS HSCs 23,[57][58][59][60][61] . One approach has been to inhibit IRAK4 in MDS 21 .…”

Section: Discussionmentioning

confidence: 99%

Chronic inflammation suppresses del(5q)-like MDS HSCs via p53

Muto

Walker

Choi

et al. 2022

Preprint

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Inflammation is associated with the pathogenesis of Myelodysplastic syndromes (MDS). Emerging evidence suggests that MDS hematopoietic stem and progenitor cells (HSPCs) exhibit an altered response to systemic low-grade inflammation, which contributes to their competitive advantage over wild-type HSPCs and ensuing hematopoietic defects. Deletion of the long arm of chromosome 5 (del(5q)) is the most common chromosomal abnormality in patients with MDS. Although this subtype of MDS contains several haploinsufficient genes that directly impact innate immune signaling, the effects of an inflammatory milieu on del(5q) MDS HSPCs remains poorly defined. Utilizing a model of del(5q)-like MDS, wherein two 5q genes, miR-146a and TIFAB, are deleted, we found that chronic low-grade inflammation impaired the function of del(5q)-like MDS HSPCs and contributed to a more severe disease. The del(5q)-like MDS HSPCs exposed to chronic inflammation became less quiescent, but without changes in cell viability. In response to inflammation, mouse and human del(5q) MDS HSPCs activated a partial p53 response. The impaired function and reduced cellular quiescence of del(5q) MDS HSPCs exposed to inflammation could be restored by deletion of p53. Since TP53 mutations are highly enriched in del(5q) AML patients following an initial MDS diagnosis, increased p53 activation in del(5q) MDS HSPCs due to inflammation may create a selective pressure for genetic inactivation of p53. These findings uncover the contribution of systemic inflammation on dyshematopoiesis in del(5q) MDS and provide a potential explanation for acquired p53 mutations in myeloid malignancies with del(5q).

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“…CD81 has been associated with a poor prognosis in AML (53) and is also a known marker in B-ALL (54, 55) while the E2 family of a ubiquitin-conjugating enzyme, UBE2s has a role in the cell cycle progression (56). AML cells are dependent on UBE2N-dependent oncogenic immune signaling states (57). DEG-associated pathway analysis showed that Sirtuin signaling, p38 MPAK signaling, and PI3K signaling were upregulated in B/My MPAL blasts.…”

Section: Discussionmentioning

confidence: 99%

Single Cell RNA Sequencing Driven Characterization of Pediatric Mixed Phenotype Acute Leukemia

Mumme

Raikar

Bhasin

et al. 2022

Preprint

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BackgroundMixed phenotype acute leukemia (MPAL) is a rare subgroup of leukemia characterized by blast cells that display both myeloid and lymphoid lineage features, making this cancer difficult to diagnose and treat. A deeper characterization of MPAL at the molecular level is essential to better understand similarities/differences to the more common and better-studied leukemias, acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Therefore, we performed single-cell RNA sequencing (scRNAseq) on MPAL bone marrow (BM) samples in an attempt to develop a more granular map of the MPAL microenvironment landscape.MethodsWe analyzed ∼16,000 cells from five pediatric MPAL BM samples collected at diagnosis to generate a single-cell transcriptomic landscape of B/Myeloid (B/My) and T/Myeloid (T/My) MPAL blasts and associated microenvironment cells. Cell clusters were identified using principal component analysis and uniform manifold approximation and projection (UMAP). Unsupervised analysis was performed to determine the overall relationship among B/My MPAL, T/My MPAL, and other acute leukemias – B-ALL, T-ALL, and AML. Supervised differentially expressed gene (DEG) analysis was performed to identify B/My and T/My MPAL blast-specific signatures. MPAL sample transcriptome profiles were compared with normal BM stem and immune cells to identify MPAL-specific dysregulation. Gene set enrichment analysis (GSEA) was performed, and significantly enriched pathways were compared in MPAL subtypes. Comparative analysis was performed on diagnostic samples based on their future minimal residual disease (MRD) and relapse status.ResultsB/My MPAL and T/My MPAL blasts displayed distinct subtype-specific blast signatures. UMAP analysis revealed that B/My MPAL samples had greater overlap with B-ALL samples, while T/My MPAL samples clustered separately from other acute leukemia subtypes. Genes overexpressed in both MPAL subtypes’ blasts compared to other leukemias and healthy controls included PLIN2, CD81, and UBE2S. B/My MPAL blast-specific genes included IRS2, SMIM3, and HBEGF, whereas T/My MPAL blast-overexpressed genes included IER5, BOD1L1, and HPGD. Sirtuin signaling, p38 MPAK signaling, and PI3K signaling pathways were upregulated in B/My MPAL blasts while oxidative phosphorylation and Rho family GTPases signaling pathways were upregulated in T/My MPAL blasts. Transcriptomic, pathways, and cell communication level differences were observed in the MPAL samples based on future MRD and clinical outcome status.ConclusionsWe have for the first time described the single-cell landscape of pediatric MPAL and demonstrate that B/My and T/My MPAL have unique scRNAseq profiles distinct from each other as well as from ALL and AML.

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Blocking UBE2N abrogates oncogenic immune signaling in acute myeloid leukemia

Cited by 16 publications

References 104 publications

Dysregulated innate immune signaling cooperates with RUNX1 mutations to transform an MDS-like disease to AML

Dysregulated innate immune signaling cooperates with RUNX1 mutations to transform an MDS-like disease to AML

Chronic inflammation suppresses del(5q)-like MDS HSCs via p53

Single Cell RNA Sequencing Driven Characterization of Pediatric Mixed Phenotype Acute Leukemia

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