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RUNX1 mutations lead to a myeloid differentiation block by altering the RUNX1 transcriptional program

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE111919 | GEO | 2019/02/06

REPOSITORIES: GEO

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RUNX1 mutations lead to a myeloid differentiation block by altering the RUNX1 transcriptional program (ChIP-Seq)

Project description:Mutations in the RUNX1 gene (RUNX1mut) have been established in myelodysplasia (MDS), de novo and secondary acute myeloid leukaemia (AML), and are in general associated with an unfavourable clinical outcome. Familial RUNX1 mutations are associated with familial thrombocytopenia and these patients have a predisposition to AML development. However, a number of studies have been performed so far in mice which might be distinct from the human hematopoietic system. Therefore we studied the cellular phenotypes, the RUNX1 binding pattern and expression profile induced by RUNX1mut in cord blood (CB) CD34+ cells and induced pluripotent stem cell (iPSC) and compared these findings to primary RUNX1mut AML’s.

2019-02-06 | GSE111917 | GEO

RUNX1 mutations lead to a myeloid differentiation block by altering the RUNX1 transcriptional program (RNA-Seq)

2019-02-06 | GSE111918 | GEO

RUNX1 mutations lead to a myeloid differentiation block by altering the RUNX1 transcriptional program

Project description:RUNX1 mutations lead to a myeloid differentiation block by altering the RUNX1 transcriptional program

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RUNX1 mutations lead to a myeloid differentiation block by altering the RUNX1 transcriptional program (RNA-Seq)

Project description:RUNX1 mutations lead to a myeloid differentiation block by altering the RUNX1 transcriptional program (RNA-Seq)

| PRJNA438539 | ENA

RUNX1 mutations lead to a myeloid differentiation block by altering the RUNX1 transcriptional program (ChIP-Seq)

Project description:RUNX1 mutations lead to a myeloid differentiation block by altering the RUNX1 transcriptional program (ChIP-Seq)

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C-terminal Mutations in RUNX1 Induce Differentiation Block and Alter Transcription through Changes in Enhancer-Promoter Interactions

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-05-29 | GSE236644 | GEO

RUNX1 mutations enhance self-renewal and block granulocytic differentiation in human in vitro models and primary AMLs.

Project description:To unravel molecular mechanisms by which Runt-related transcription factor 1 (RUNX1) mutations contribute to leukemic transformation, we introduced the RUNX1-S291fs300X mutation in human CD34+ stem/progenitor cells and in human induced pluripotent stem cells (iPSCs). In both models, RUNX1mut overexpression strongly impaired myeloid commitment. Instead, self-renewal was enhanced, as shown, by increased long-term culture-initiating cell frequencies and enhanced colony-forming cell replating capacity. Long-term suspension cultures with RUNX1mut-transduced cord blood (CB) CD34+ cells continued for more than 100 days, during which the cells displayed an immature granulocyte-macrophage progenitor-like CD34+/CD123+/CD45RA+ phenotype. The CD34+/CD38- hematopoietic stem cell (HSC) population most likely acted as cell of origin, as HSCs provided the best long-term proliferative potential on overexpression of RUNX1mut. CEBPA expression was reduced in RUNX1mut cells, and reexpression of CEBPA partly restored differentiation. RNA-seq analysis on CB/iPSC systems and on primary patient samples confirmed that RUNX1 mutations induce a myeloid differentiation block, and that a common set of RUNX1mut-upregulated target genes was strongly enriched for gene ontology terms associated with nucleosome assembly and chromatin structure. Interestingly, in comparison with AML1-ETO binding in acute myeloid leukemias (AMLs), we found significantly distinct genomic distribution and differential expression for RUNX1mut of genes such as TCF4, MEIS1, and HMGA2 that may potentially contribute to the underlying difference in clinical outcomes between RUNX1mut and AML1-ETO patients. In conclusion, RUNX1mut appears to induce a specific transcriptional program that contributes to leukemic transformation.

| S-EPMC6373749 | biostudies-literature

RUNX1 mutations in blast-phase chronic myeloid leukemia associate with distinct phenotypes, transcriptional profiles, and drug responses.

Project description:Blast-phase chronic myeloid leukemia (BP-CML) is associated with additional chromosomal aberrations, RUNX1 mutations being one of the most common. Tyrosine kinase inhibitor therapy has only limited efficacy in BP-CML, and characterization of more defined molecular subtypes is warranted in order to design better treatment modalities for this poor prognosis patient group. Using whole-exome and RNA sequencing we demonstrate that PHF6 and BCORL1 mutations, IKZF1 deletions, and AID/RAG-mediated rearrangements are enriched in RUNX1mut BP-CML leading to typical mutational signature. On transcriptional level interferon and TNF signaling were deregulated in primary RUNX1mut CML cells and stem cell and B-lymphoid factors upregulated giving a rise to distinct phenotype. This was accompanied with the sensitivity of RUNX1mut blasts to CD19-CAR T cells in ex vivo assays. High-throughput drug sensitivity and resistance testing revealed leukemia cells from RUNX1mut patients to be highly responsive for mTOR-, BCL2-, and VEGFR inhibitors and glucocorticoids. These findings were further investigated and confirmed in CRISPR/Cas9-edited homozygous RUNX1-/- and heterozygous RUNX1-/mut BCR-ABL positive cell lines. Overall, our study provides insights into the pathogenic role of RUNX1 mutations and highlights personalized targeted therapy and CAR T-cell immunotherapy as potentially promising strategies for treating RUNX1mut BP-CML patients.

| S-EPMC8024199 | biostudies-literature

Different mutant RUNX1 oncoproteins program alternate haematopoietic differentiation trajectories.

Project description:Mutations of the haematopoietic master regulator RUNX1 are associated with acute myeloid leukaemia, familial platelet disorder and other haematological malignancies whose phenotypes and prognoses depend upon the class of the RUNX1 mutation. The biochemical behaviour of these oncoproteins and their ability to cause unique diseases has been well studied, but the genomic basis of their differential action is unknown. To address this question we compared integrated phenotypic, transcriptomic, and genomic data from cells expressing four types of RUNX1 oncoproteins in an inducible fashion during blood development from embryonic stem cells. We show that each class of mutant RUNX1 deregulates endogenous RUNX1 function by a different mechanism, leading to specific alterations in developmentally controlled transcription factor binding and chromatin programming. The result is distinct perturbations in the trajectories of gene regulatory network changes underlying blood cell development which are consistent with the nature of the final disease phenotype. The development of novel treatments for RUNX1-driven diseases will therefore require individual consideration.

| S-EPMC7812315 | biostudies-literature

Cdk6 blocks myeloid differentiation by interfering with Runx1 DNA binding and Runx1-C/EBPalpha interaction.

Project description:Interactions between the cell cycle machinery and transcription factors play a central role in coordinating terminal differentiation and proliferation arrest. We here show that cyclin-dependent kinase 6 (Cdk6) is specifically expressed in proliferating hematopoietic progenitor cells, and that Cdk6 inhibits transcriptional activation by Runx1, but not C/EBPalpha or PU.1. Cdk6 inhibits Runx1 activity by binding to the runt domain of Runx1, interfering with Runx1 DNA binding and Runx1-C/EBPalpha interaction. Cdk6 expression increased myeloid progenitor proliferation, and inhibited myeloid lineage-specific gene expression and terminal differentiation in vitro and in vivo. These effects of Cdk6 did not require Cdk6 kinase activity. Cdk6-mediated inhibition of granulocytic differentiation could be reversed by excess Runx1, consistent with Runx1 being the major target for Cdk6. We propose that Cdk6 downregulation in myeloid progenitors releases Runx1 from Cdk6 inhibition, thereby allowing terminal differentiation. Since Runx transcription factors play central roles in hematopoietic, neuronal and osteogenic lineages, this novel, noncanonical Cdk6 function may control terminal differentiation in multiple tissues and cell types.

| S-EPMC1864973 | biostudies-literature

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