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A KMT2A-AFF1 gene regulatory network highlights the role of core transcription factors and reveals the regulatory logic of key downstream target genes.

ABSTRACT: A KMT2A-AFF1 gene regulatory network highlights the role of core transcription factors and reveals the regulatory logic of key downstream target genes.

PROVIDER: PRJNA635660 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11868305_1.fastq.gz	Fastqsanger.gz
	SRR11868305_2.fastq.gz	Fastqsanger.gz
	SRR11868306_1.fastq.gz	Fastqsanger.gz
	SRR11868306_2.fastq.gz	Fastqsanger.gz
	SRR11868307_1.fastq.gz	Fastqsanger.gz

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A KMT2A-AFF1 gene regulatory network highlights the role of core transcription factors and reveals the regulatory logic of key downstream target genes [ChIP-seq]

Project description:Regulatory interactions mediated by transcription factors (TFs) make up complex networks that control cellular behavior. Fully understanding these gene regulatory networks (GRNs) offers greater insight into the consequences of disease-causing perturbations than can be achieved by studying single TF binding events in isolation. Chromosomal translocations of the lysine methyltransferase 2A (KMT2A) produce KMT2A fusion proteins such as KMT2A-AFF1 (also known as MLL-AF4), causing poor prognosis acute lymphoblastic leukemias (ALLs) that sometimes relapse as acute myeloid leukemias (AMLs). KMT2A-AFF1 is thought to drive leukemogenesis through direct binding and inducing aberrant overexpression of key gene targets, such as the anti-apoptotic factor BCL2 and the proto-oncogene MYC. However, studying direct binding alone doesn’t allow for network generated regulatory outputs, including the indirect induction of gene repression. To better understand the KMT2A-AFF1 driven regulatory landscape, we integrated ChIP-seq, patient RNA-seq and CRISPR essentiality screens to generate a model GRN. This GRN identified several key transcription factors, including RUNX1, that regulate target genes downstream of KMT2A-AFF1 using feed-forward loop (FFL) and cascade motifs. A core set of nodes are present in both ALL and AML, and CRISPR screening revealed several factors that help mediate response to the drug venetoclax. Using our GRN, we then identified an KMT2A-AFF1:RUNX1 cascade that represses CASP9, as well as KMT2A-AFF1 driven FFLs that regulate BCL2 and MYC through combinatorial TF activity. This illustrates how our GRN can be used to better connect KMT2A-AFF1 behavior to downstream pathways that contribute to leukemogenesis, and potentially predict shifts in gene expression that mediate drug response.

2021-05-23 | GSE151386 | GEO

A KMT2A-AFF1 gene regulatory network highlights the role of core transcription factors and reveals the regulatory logic of key downstream target genes [RNA-seq]

2021-05-23 | GSE151385 | GEO

A KMT2A-AFF1 gene regulatory network highlights the role of core transcription factors and reveals the regulatory logic of key downstream target genes [CRISPR sgRNA screen]

2021-05-23 | GSE151389 | GEO

A KMT2A-AFF1 gene regulatory network highlights the role of core transcription factors and reveals the regulatory logic of key downstream target genes [ChIP-seq]

Project description:A KMT2A-AFF1 gene regulatory network highlights the role of core transcription factors and reveals the regulatory logic of key downstream target genes [ChIP-seq]

| PRJNA635662 | ENA

A KMT2A-AFF1 gene regulatory network highlights the role of core transcription factors and reveals the regulatory logic of key downstream target genes [RNA-seq]

Project description:A KMT2A-AFF1 gene regulatory network highlights the role of core transcription factors and reveals the regulatory logic of key downstream target genes [RNA-seq]

| PRJNA635661 | ENA

A KMT2A-AFF1 gene regulatory network highlights the role of core transcription factors and reveals the regulatory logic of key downstream target genes [CRISPR sgRNA screen]

Project description:A KMT2A-AFF1 gene regulatory network highlights the role of core transcription factors and reveals the regulatory logic of key downstream target genes [CRISPR sgRNA screen]

| PRJNA635663 | ENA

Ontogeny-specific induction of the KMT2A::AFF1-fusion drives development of a distinct CD24 positive pre-leukemic state

Project description:Infant Acute Lymphoblastic Leukemia (ALL) driven by the KMT2A::AFF1 onco-fusion is an aggressive, poor prognosis disease with few co-operative mutations. The fusion originates in utero, yet the embryonic initiating steps of disease development remain poorly understood. Here, we present a novel murine KMT2A::AFF1 model, that provides key insights into KMT2A::AFF1 pre-leukemia, relevant to human disease. The model enables precise oncogene induction, and upon targeting hematopoietic stem and progenitor cells (HSPCs) a selective negative impact on proliferation of hematopoietic stem cells (HSCs) was observed, regardless of developmental state during induction. However, a unique CD24 PreProB subset expanded exclusively within the KMT2A::AFF1 embryonic context. This population was absent when targeting lymphoid progenitors, highlighting the importance of the cell of origin for leukemic development. The CD24 PreProB subset displayed key features of pre-leukemic stem cells, including lineage plasticity and aberrant engraftment ability. In line with their pre-malignant phenotype, single-cell transcriptomics revealed a signature consistent with stemness, and notable, up-regulation of Hmga2, a regulator of self-renewal. The signature was critically transferable to human KMT2A::AFF1 patients. Furthermore, given that CD24 is a potential therapeutic target, our findings uncover a distinct embryonic pre-leukemic state with direct relevance to human disease.

2025-06-20 | GSE251658 | GEO

A KMT2A-AFF1 gene regulatory network highlights the role of core transcription factors and reveals the regulatory logic of key downstream target genes.

Project description:Regulatory interactions mediated by transcription factors (TFs) make up complex networks that control cellular behavior. Fully understanding these gene regulatory networks (GRNs) offers greater insight into the consequences of disease-causing perturbations than can be achieved by studying single TF binding events in isolation. Chromosomal translocations of the lysine methyltransferase 2A (KMT2A) gene produce KMT2A fusion proteins such as KMT2A-AFF1 (previously MLL-AF4), causing poor prognosis acute lymphoblastic leukemias (ALLs) that sometimes relapse as acute myeloid leukemias (AMLs). KMT2A-AFF1 drives leukemogenesis through direct binding and inducing the aberrant overexpression of key genes, such as the anti-apoptotic factor BCL2 and the proto-oncogene MYC However, studying direct binding alone does not incorporate possible network-generated regulatory outputs, including the indirect induction of gene repression. To better understand the KMT2A-AFF1-driven regulatory landscape, we integrated ChIP-seq, patient RNA-seq, and CRISPR essentiality screens to generate a model GRN. This GRN identified several key transcription factors such as RUNX1 that regulate target genes downstream of KMT2A-AFF1 using feed-forward loop (FFL) and cascade motifs. A core set of nodes are present in both ALL and AML, and CRISPR screening revealed several factors that help mediate response to the drug venetoclax. Using our GRN, we then identified a KMT2A-AFF1:RUNX1 cascade that represses CASP9, as well as KMT2A-AFF1-driven FFLs that regulate BCL2 and MYC through combinatorial TF activity. This illustrates how our GRN can be used to better connect KMT2A-AFF1 behavior to downstream pathways that contribute to leukemogenesis, and potentially predict shifts in gene expression that mediate drug response.

| S-EPMC8256865 | biostudies-literature

PROM1/CD133 MARKS A PROLIFERATIVE STEM CELL LIKE POPULATION OF BLASTS IN KMT2A REARRANGED INFANT ALL

Project description:Among pediatric acute lymphoblastic leukemias (ALL), KMT2A-rearranged infant ALL (KMT2Ar iALL) carries a particularly poor prognosis due to high rates of treatment-refractory or relapsing disease. Mechanistically, KMT2Ar drives aggressive disease through epigenetic dysregulation of multiple genes as a direct effect of expression of KMT2A-fusion proteins, most commonly KMT2A::AFF1, in leukemic cells. We previously showed that one of the top 2 most dysregulated genes, PROM1 (Prominin-1), encodes the cell surface protein prominin-1/CD133 and that this is essential for proliferation of KMT2A::AFF1+ cell lines. Here we show that PROM1 gene expression and cell surface CD133 expression specifically mark a highly proliferative subset of KMT2A::AFF1 blasts both in primary patient samples and in our highly physiologically relevant, primary human fetal liver HSPC-derived KMT2A::AFF1 ALL model (CRISPRKMT2A::AFF1 ALL). CD133+ CRISPRKMT2A::AFF1 blasts, but not CD133- CRISPRKMT2A::AFF1 blasts, exhibit a stem-cell gene expression profile and drive more aggressive disease in vivo. Furthermore, CRISPR-mediated inactivation of PROM1 reduces leukemic proliferation and prolongs survival of mice transplanted with CRISPRKMT2A::AFF1 blasts. These data show that PROM1/CD133 expression has an important functional role in CRISPRKMT2A::AFF1 ALL, and supports targeting PROM1/CD133 by pharmacological or immunotherapy-based approaches in KMT2A::AFF1 iALL. 

2025-10-01 | GSE278786 | GEO

PROLIFERATIVE STEM CELL LIKE POPULATION OF BLASTS IN KMT2A REARRANGED INFANT ALL

Project description:Among pediatric acute lymphoblastic leukemias (ALL), KMT2A-rearranged infant ALL (KMT2Ar iALL) carries a uniquely poor prognosis due to high rates of treatment-refractory or relapsing disease. It is important to understand how KMT2A mutations drive such aggressive disease in order to develop more effective and less toxic therapies. The PROM1 gene, encoding the pentaspan glycoprotein prominin-1/CD133, is activated by the direct action of the most common KMT2A fusion protein; KMT2A::AFF1 (MLL-AF4). CD133 expression is essential for proliferation of KMT2A::AFF1+ cell lines but its role in primary disease remains unclear with heterogenous expression seen in iALL patient samples. To clarify the role of CD133 in KMT2Ar iALL we have used a highly physiological primary human fetal liver derived model (CRISPRKMT2A::AFF1 ALL) which recapitulates CD133 heterogeneity. We show that CD133 expression marks a highly proliferative subset of CRISPRKMT2A::AFF1 blasts with a stem-cell gene expression profile capable of causing more aggressive disease in vivo. CRISPR inactivation of PROM1 limits leukemic proliferation, suggesting a functional role in our model and providing a strong rationale for targeting therapies against CD133.

2025-06-26 | GSE295316 | GEO

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