A5000805926- Acute Myeloid Leukemia Research
- RNA Interference and Gene Delivery
- RNA modifications and cancer
- RNA Research and Splicing
- Cancer-related molecular mechanisms research
- Extracellular vesicles in disease
- Synthesis of Tetrazole Derivatives
- Hematopoietic Stem Cell Transplantation
- Chronic Myeloid Leukemia Treatments
- Histone Deacetylase Inhibitors Research
- Cancer-related gene regulation
- Epigenetics and DNA Methylation
- Dupuytren's Contracture and Treatments
- Ferroptosis and cancer prognosis
- Immune Cell Function and Interaction
- Immunodeficiency and Autoimmune Disorders
- Endoplasmic Reticulum Stress and Disease
- Prostate Cancer Treatment and Research
- Chronic Lymphocytic Leukemia Research
- Mycobacterium research and diagnosis
Institute of Cancer Research
2024
Queen Mary University of London
2020-2023
MRC Centre for Regenerative Medicine
2019-2022
University of Edinburgh
2019-2022
Highlights•YTHDF2 is highly expressed across human AML and essential for leukemia initiation•YTHDF2 shortens the half-life of m6A-modified transcripts in AML•Loss YTHDF2 expands HSCs but does not derail hematopoiesis•YTHDF2 protects cells from apoptosis by downregulating TNFR2SummaryAcute myeloid (AML) an aggressive clonal disorder hematopoietic stem (HSCs) primitive progenitors that blocks their differentiation, generating self-renewing leukemic (LSCs). Here, we show mRNA m6A reader...
The mRNA N6-methyladenosine (m6A) modification has emerged as an essential regulator of normal and malignant hematopoiesis. Inactivation the m6A reader YTHDF2, which recognizes m6A-modified transcripts to promote m6A-mRNA degradation, results in hematopoietic stem cell (HSC) expansion compromises acute myeloid leukemia. Here we investigate long-term impact YTHDF2 deletion on HSC maintenance multilineage We demonstrate that Ythdf2-deficient HSCs from young mice fail upon serial...
Resistance to standard and novel therapies remains the main obstacle cure in acute myeloid leukaemia (AML) is often driven by metabolic adaptations which are therapeutically actionable. Here we identify inhibition of mannose-6-phosphate isomerase (MPI), first enzyme mannose metabolism pathway, as a sensitizer both cytarabine FLT3 inhibitors across multiple AML models. Mechanistically, connection between fatty acid metabolism, that mediated via preferential activation ATF6 arm unfolded...
Hematopoietic stem cells (HSCs) reside at the apex of hematopoietic differentiation hierarchy and sustain multilineage hematopoiesis. Here, we show that transcriptional regulator CITED2 is essential for life-long HSC maintenance. While hematopoietic-specific Cited2 deletion has a minor impact on steady-state hematopoiesis, Cited2-deficient HSCs are severely depleted in young mice fail to expand upon aging. Moreover, although they home normally bone marrow, reconstitute hematopoiesis...
ABSTRACT Peptidylarginine deiminases (PADIs) are strongly associated with the development of autoimmunity, neurodegeneration and cancer but their physiological roles ill-defined. The nuclear deiminase PADI4 regulates pluripotency in mammalian pre-implantation embryo its function tissue is unknown. primarily expressed bone marrow, as part a self-renewal-associated gene signature. It has been shown to regulate proliferation multipotent haematopoietic progenitors proposed impact on...
Abstract Peptidylarginine deiminases (PADIs, or PADs) are emerging as key regulators of human physiology and pathophysiology. The nuclear deiminase PADI4 regulates embryonic stem cell pluripotency, however its role in adult cells is unknown. expressed most highly the bone marrow (BM), where it found part a self-renewal-associated gene signature shown to modulate function critical transcriptional such Tal1 c-Myc, suggesting that haematopoietic development regeneration. We investigated...
Abstract Resistance to standard and novel therapies remains the main obstacle cure in acute myeloid leukemia (AML) is often driven by metabolic adaptations which are therapeutically actionable. Here we identify inhibition of mannose-6-phosphate isomerase (MPI), first enzyme mannose metabolism pathway, as a sensitizer both cytarabine FLT3 inhibitors across multiple AML models. Mechanistically, connection between fatty acid metabolism, that mediated via preferential activation ATF6 arm...