Proliferative stem cell-like population of blasts in KMT2A-rearranged infant ALL [scRNA-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1258267 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR33414788_1.fastq.gz | Fastqsanger.gz | |||
| SRR33414788_2.fastq.gz | Fastqsanger.gz |
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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
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.
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Project description:PROLIFERATIVE STEM CELL LIKE POPULATION OF BLASTS IN KMT2A REARRANGED INFANT ALL
| PRJNA1254185 | ENA
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.
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Project description:PROM1/CD133 MARKS A PROLIFERATIVE STEM CELL LIKE POPULATION OF BLASTS IN KMT2A REARRANGED INFANT ALL
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Project description:The KMT2A rearranged B lineage infant ALL cell line SEM was treated with the proteasome inhibitor bortezomib followed by a multiplexed mass spectrometry-based proteomic analysis at multiple time points (0, 6, 12, 16, and 20 hours) over 20 hours to further understand the cellular response of these cells to proteasome inhibition.
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Project description:Genome-wide methylation profiling was performed on six cell lines derived from infants with KMT2A-rearranged ALL following treatment with three hypomethylating drugs (azacitidine, decitabine and zebularine) administered at low doses for 72 hours in vitro. We identified drug-specific and common differentially methylated regions and validated differentially expressed genes located within such regions, indicating commonalities in pathways targeted by azacitidine and decitabine in KMT2A-rearranged infant ALL. Of the three drugs, the most significant degree of hypomethylation was induced by decitabine followed by azacitidine, whereas zebularine did not exert a significant hypomethylating effect.
2022-12-31 | GSE198679 | GEO
Project description:Acute myeloid leukemia (AML) is a disease with poor outcome but patients harbouring certain chromosomal rearrangements or complex karyotypes have particularly adverse prognosis. For these patients, targeted therapies have not yet made a significant clinical impact. To understand the molecular landscape of poor risk AML we profiled 55 poor risk AML patients using a multiomics approach that included transcriptomics (n=39), proteomics (n=55), phosphoproteomics (n=55) and an ex vivo drug sensitivity screening (482 compounds tested in at least 30 patients). We identified a phosphoproteomics signature that define two biologically distinct groups of KMT2A rearranged leukaemia, which we term MLLGA and MLLGB. MLLGA presented increased DOT1L phosphorylation, HOXA gene expression, CDK1 activity and phosphorylation of proteins involved in RNA metabolism, replication and DNA damage when compared to MLLGB and no KMT2A rearranged samples. MLLGA was particularly sensitive to 15 compounds including genotoxic drugs and inhibitors of mitotic kinases and IMPDH relative to other cases. The expression of IMPDH2 and multiple nucleolar proteins was higher in MLLGA and correlated with the response to IMPDH inhibition in KMT2A rearranged leukaemia, suggesting a role of the nucleolar activity in sensitivity to IMPDH inhibition. In summary, our multilayer molecular profiling of poor risk AML matched to the response to hundreds of compounds identified a phosphoproteomics signature that define two biologically and phenotypically distinct groups of KMT2A rearranged leukaemia. These data provide a rationale for the development of specific therapies for KMT2A subgroups characterised by the MLLGA phosphoproteomics signature identified in this study.
2023-03-11 | PXD036669 | Pride
Project description:Transcriptomic profiling was performed on six cell lines derived from infants with KMT2A-rearranged ALL following treatment with two hypomethylating drugs (azacitidine and decitabine) administered at low doses for 72 hours in vitro. We identified changes in gene expression following treatment with hypomethylating agents, with decitabine exerting a greater effect than azacitidine.
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Project description:Acute Lymphoblastic Leukemia (ALL) in infants (<1 year of age) is characterized by a high incidence of MLL translocations which is associated with a poor prognosis. Contributing to this poor prognosis is cellular drug resistance, especially to glucocorticoids like prednisolone. Although in vitro prednisolone resistance mechanisms have been proposed in pediatric ALL, it has never been studied in MLL-rearranged infant ALL, which are highly resistant to glucocorticoids in vitro and in vivo. We analyzed primary MLL-rearranged infant ALL expression profiles, which were either in vitro prednisolone-resistant or prednisolone-sensitive, in order to study in vitro prednisolone resistance.
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