{"id":"8bdf03ea-5c82-584a-860b-2f4f9a237c8c","stable_key":"a2968a2f-5b00-5212-8b8c-8a4262bcb149:atra-with-ascorbate-reduces-lsc-self-renewal","predicate":"combined_with_ascorbate_reduces","statement":"All-trans retinoic acid together with ascorbate induced differentiation and inhibited leukaemia stem cell self-renewal in a TET2-dependent manner in primary human acute-myeloid-leukaemia models, sensitised the cells to targeted therapies in vivo and improved survival.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"negative","is_public":true,"mechanism_event_id":"3fd3b5f3-d000-5cab-9a97-425f7ef14e6d","mechanism_event_label":"All-trans retinoic acid together with ascorbate induced differentiation and inhibited leukaemia stem cell self-renewal in a TET2-dependent manner in primary human acute-myeloid-leukaemia models, sensitised the cells to targeted therapies in vivo and improved survival.","subject":{"id":"05487b29-8c59-5af8-83cf-cf9c79c5ecb8","slug":"all-trans-retinoic-acid","display_name":"All-trans-retinoic acid","entity_type_key":"small_molecule"},"object":{"id":"cbb52c64-b611-576a-8502-9b7fd9ee4716","slug":"human-aml-leukaemia-stem-cell-self-renewal","display_name":"Leukaemia stem cell self-renewal in human acute myeloid leukaemia models","entity_type_key":"cellular_process"},"evidence_count":1,"mechanism_event":{"id":"3fd3b5f3-d000-5cab-9a97-425f7ef14e6d","stable_key":"a2968a2f-5b00-5212-8b8c-8a4262bcb149:atra-with-ascorbate-reduces-lsc-self-renewal-event","event_type":"observed_relationship","label":"All-trans retinoic acid together with ascorbate induced differentiation and inhibited leukaemia stem cell self-renewal in a TET2-dependent manner in primary human acute-myeloid-leukaemia models, sensitised the cells to targeted therapies in vivo and improved survival.","description":"Retinoic acid and vitamin C together worked better than either was expected to alone.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"05487b29-8c59-5af8-83cf-cf9c79c5ecb8","slug":"all-trans-retinoic-acid","display_name":"All-trans-retinoic acid","entity_type_key":"small_molecule"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"cbb52c64-b611-576a-8502-9b7fd9ee4716","slug":"human-aml-leukaemia-stem-cell-self-renewal","display_name":"Leukaemia stem cell self-renewal in human acute myeloid leukaemia models","entity_type_key":"cellular_process"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"38d0c4d9-53d1-5239-bfe3-c1b5e9b79085","slug":"ascorbate","display_name":"L-Ascorbate","entity_type_key":"small_molecule"},"role":"co-administered agent","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"5433ea92-f679-5b25-a872-cb8a636ae4e1","slug":"tet2-human","display_name":"Human TET2","entity_type_key":"protein"},"role":"enzyme the effect depends on","stoichiometry":null,"state_label":"","sequence_order":3,"notes":""}]},"contexts":[{"dimension":"duration","value_text":"In vivo to survival","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_condition","value_text":"All-trans retinoic acid administered","comparator":"Untreated or single-agent primary human AML models","unit":null,"notes":"Condition belongs to the full experimental contrast; do not separate a joint intervention.","entity":{"slug":"all-trans-retinoic-acid","display_name":"All-trans-retinoic acid","entity_type_key":"small_molecule"}},{"dimension":"experimental_condition","value_text":"Ascorbate administered","comparator":"Untreated or single-agent primary human AML models","unit":null,"notes":"Condition belongs to the full experimental contrast; do not separate a joint intervention.","entity":{"slug":"ascorbate","display_name":"L-Ascorbate","entity_type_key":"small_molecule"}},{"dimension":"experimental_contrast","value_text":"{\"intervention\": \"All-trans retinoic acid plus ascorbate\", \"comparator\": \"Untreated or single-agent primary human AML models\", \"endpoint\": \"Leukaemia stem cell self-renewal and survival\", \"effect_direction\": \"decrease\", \"combination\": \"joint\", \"conditions\": [{\"entity_slug\": \"all-trans-retinoic-acid\", \"state\": \"All-trans retinoic acid administered\"}, {\"entity_slug\": \"ascorbate\", \"state\": \"Ascorbate administered\"}]}","comparator":null,"unit":null,"notes":"Explicit extracted experimental comparison; source-derived draft.","entity":null},{"dimension":"experimental_model","value_text":"Tet1/2/3-deficient mice and primary human AML models","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"All-trans retinoic acid combined with ascorbate","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"A joint intervention: the two agents were given together and this record cannot be read as the separate effect of either. TET2-dependence was shown with TET-deficient mice, which removes three paralogs rather than TET2 alone.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"organism","value_text":"Mus musculus and Homo sapiens","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"Retinoic acid and vitamin C together worked better than either was expected to alone.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[celrep-2025] Retinoic acid and ascorbate synergize to suppress myeloid leukemia via TET2 activation (2025). https://pubmed.ncbi.nlm.nih.gov/41037397/ DOI: 10.1016/j.celrep.2025.116379","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue","value_text":"Leukaemia stem cells","comparator":null,"unit":null,"notes":"","entity":null}],"evidence":[{"id":"715cd3ff-f226-5073-8369-547ebe38ea25","evidence_kind":"source_excerpt","locator":"Lines 153-161","start_line":153,"end_line":161,"excerpt":"## atra-with-ascorbate-reduces-lsc-self-renewal\nAll-trans retinoic acid together with ascorbate induced differentiation and inhibited leukaemia stem cell self-renewal in a TET2-dependent manner in primary human acute-myeloid-leukaemia models, sensitised the cells to targeted therapies in vivo and improved survival.\nModel/species: Tet1/2/3-deficient mice and primary human AML models\nOrganism: Mus musculus and Homo sapiens\nTissue/system: Leukaemia stem cells\nExposure: All-trans retinoic acid combined with ascorbate\nDuration: In vivo to survival\nLimits: A joint intervention: the two agents were given together and this record cannot be read as the separate effect of either. TET2-dependence was shown with TET-deficient mice, which removes three paralogs rather than TET2 alone.\nPrimary reference: [celrep-2025] Retinoic acid and ascorbate synergize to suppress myeloid leukemia via TET2 activation (2025). https://pubmed.ncbi.nlm.nih.gov/41037397/ DOI: 10.1016/j.celrep.2025.116379","model_system":"Tet1/2/3-deficient mice and primary human AML models","directness":"reported_statement","verification_status":"source_derived_draft","notes":"","relationship":"supports","weight":1.0,"link_notes":"","source":{"id":"c0b9b176-985b-55c7-b8f5-f3ca16a7ddfe","stable_key":"import-a2968a2f-5b00-5212-8b8c-8a4262bcb149","title":"TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23)","document_type":"imported_text","citation_label":"Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text.","file_path":"","sha256":"22e2c8388d4f0c1813546ba6a9ccee3fa14c0c8f578bd9bd80103c1390b2536b","revision_id":"fbc29d8d-0420-562c-bfdb-1b5af42f2d08","review_status":"unverified_draft","notes":""}}],"relations":[],"conflicts":[],"corrections":[],"research":null}