Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ABSTRACT: 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. 

ORGANISM(S): Homo sapiens

PROVIDER: GSE278786 | GEO | 2025/10/01

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

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

Proliferative stem cell-like population of blasts in KMT2A-rearranged infant ALL [scRNA-seq]

2025-06-26 | GSE296245 | GEO

H3K79me2/3 controls enhancer promoter interactions and activation of the pan-cancer stem cell marker PROM1/CD133 in MLL-AF4 leukemia cells (ATAC-seq)

Project description:MLL gene rearrangements (MLLr) are a common cause of aggressive, incurable acute lymphoblastic leukemias (ALL) in infants and children, most of which originate in utero. The most common MLLr produces an MLL-AF4 fusion protein. MLL-AF4 promotes leukemogenesis by activating key target genes, mainly through recruitment of DOT1L and increased histone H3 lysine 79 methylation (H3K79me2/3). One key MLL-AF4 target gene is PROM1 which encodes CD133 (Prominin-1). CD133 is a pentaspan transmembrane glycoprotein that represents a potential pan-cancer target as it is found on multiple cancer stem cells. Here we demonstrate that aberrant PROM1/CD133 expression is essential for leukemic cell growth, mediated by direct binding of MLL-AF4. Activation is controlled by an intragenic H3K79me2/3 enhancer element (KEE) leading to increased enhancer-promoter interactions between PROM1 and the nearby gene TAPT1. This dual locus regulation is reflected in a strong correlation of expression in leukemia. We find that in PROM1/CD133 non-expressing cells, the PROM1 locus is repressed by polycomb repressive complex 2 (PRC2) binding, associated with reduced expression of TAPT1, partially due to loss of interactions with the PROM1 locus. Together, these results provide the first detailed analysis of PROM1/CD133 regulation that explains CD133 expression in MLLr ALL.

2020-03-25 | GSE135025 | GEO

H3K79me2/3 controls enhancer promoter interactions and activation of the pan-cancer stem cell marker PROM1/CD133 in MLL-AF4 leukemia cells (ChIP-seq)

2020-03-25 | GSE135024 | GEO

H3K79me2/3 controls enhancer promoter interactions and activation of the pan-cancer stem cell marker PROM1/CD133 in MLL-AF4 leukemia cells (RNA-seq)

2020-03-25 | GSE135023 | GEO

Modelling acquired resistance to DOT1L inhibition exhibits the adaptive potential of KMT2A-rearranged Acute Lymphoblastic Leukemia’ [RNA-seq]

Project description:KMT2A-rearranged acute lymphoblastic leukemia (ALL) is an aggressive type of leukemia which represents the most common form diagnosed in infancy. Oncogenic KMT2A-fusion proteins recruit histone methyltransferase DOT1L which leads to misplaced H3K79 methylation inducing an abnormal transcriptomic landscape that favors leukemia development. Hence, inhibition of DOT1L represents an attractive therapeutic strategy. Unfortunately, the first-in-class DOT1L inhibitor pinometostat resulted in the development of resistance. To understand this resistance we established acquired resistance to DOT1L inhibition in a pediatric KMT2A::AFF1+ B-ALL cell line model that stably became ~35-fold more resistant to pinometostat. Interestingly, while becoming almost completely independent of DOT1L-mediated H3K79 methylation, these cells remained fully dependent on the physical presence of DOT1L, HOXA9, as well as the KMT2A::AFF1 fusion protein. Further characterization of these cells using RNA-, ChIP-, and ATAC-sequencing analyses revealed that acquired resistance to DOT1L inhibition leads to a selective loss of KMT2A-fusion driven epigenetic regulation and expression of genes such as PROM1 (encoding the hematopoietic/leukemia stem cell marker CD133) and its enhancer TAPT1, as well as other putative KMT2A::AFF1 target genes such as RUNX2, PRSS12, ZC3H12, and GNAQ. In contrast, the levels of H3K79me2 and expression of other KMT2A::AFF1 target genes, including HOXA9, MEIS1, and CDK6 remained unaffected. Concomitantly, pinometostat-resistant KMT2A::AFF1+ B-ALL cells showed upregulation of genes associated with a myeloid immunophenotype, including CD33, LILRB4/CD85k, MPEG1, CCL5, and LIMK1. Taken together, we here present a valuable model to study the adaptive potential of KMT2A-rearranged ALL upon losing dependency on one of its main oncogenic properties.

2023-09-27 | GSE230791 | GEO

Modelling acquired resistance to DOT1L inhibition exhibits the adaptive potential of KMT2A-rearranged Acute Lymphoblastic Leukemia’ [ChIP-seq]

2023-09-27 | GSE230806 | GEO

Modelling acquired resistance to DOT1L inhibition exhibits the adaptive potential of KMT2A-rearranged Acute Lymphoblastic Leukemia’ [ATAC-seq]

2023-09-27 | GSE230799 | GEO

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

PROM1(CD133)-dependent expressed genes from mouse embryonic DRG neurons

Project description:Prom1, also knwon as CD133 is a stem cell marker that are down-regulated during developmental process. Here we first reports that PROM1 is a regulator of expression of specific sets of genes from DRG neurons.

2020-04-02 | GSE147936 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data