{"doi":"10.1172/jci165510","title":"RAB27B controls palmitoylation-dependent NRAS trafficking and signaling in myeloid leukemia","abstract":"RAS mutations are among the most prevalent oncogenic drivers in cancers. RAS proteins propagate signals only when associated with cellular membranes as a consequence of lipid modifications that impact their trafficking. Here, we discovered that RAB27B, a RAB family small GTPase, controlled NRAS palmitoylation and trafficking to the plasma membrane, a localization required for activation. Our proteomic studies revealed RAB27B upregulation in CBL- or JAK2-mutated myeloid malignancies, and its expression correlated with poor prognosis in acute myeloid leukemias (AMLs). RAB27B depletion inhibited the growth of CBL-deficient or NRAS-mutant cell lines. Strikingly, Rab27b deficiency in mice abrogated mutant but not WT NRAS-mediated progenitor cell growth, ERK signaling, and NRAS palmitoylation. Further, Rab27b deficiency significantly reduced myelomonocytic leukemia development in vivo. Mechanistically, RAB27B interacted with ZDHHC9, a palmitoyl acyltransferase that modifies NRAS. By regulating palmitoylation, RAB27B controlled c-RAF/MEK/ERK signaling and affected leukemia development. Importantly, RAB27B depletion in primary human AMLs inhibited oncogenic NRAS signaling and leukemic growth. We further revealed a significant correlation between RAB27B expression and sensitivity to MEK inhibitors in AMLs. Thus, our studies presented a link between RAB proteins and fundamental aspects of RAS posttranslational modification and trafficking, highlighting future therapeutic strategies for RAS-driven cancers.","journal":"Journal of Clinical Investigation","year":2023,"id":321027,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":46,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9467,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1032473,"name":"Bowen Xing","orcid":"0000-0002-1244-8545","position":1,"is_corresponding":false},{"id":345633,"name":"Kaosheng Lv","orcid":"0000-0001-7998-2753","position":2,"is_corresponding":false},{"id":453085,"name":"Rachel A. O’Keefe","orcid":"0000-0003-3231-9772","position":3,"is_corresponding":false},{"id":1032916,"name":"Meng‐Fang Wu","orcid":null,"position":4,"is_corresponding":false},{"id":842539,"name":"Ruoxing Wang","orcid":"0000-0002-0733-1094","position":5,"is_corresponding":false},{"id":350133,"name":"Kaylyn M. Bauer","orcid":"0000-0002-5498-9083","position":6,"is_corresponding":false},{"id":672623,"name":"Arevik Ghazaryan","orcid":"0000-0002-4718-4164","position":7,"is_corresponding":false},{"id":107239,"name":"George M. Burslem","orcid":"0000-0002-2812-983X","position":8,"is_corresponding":false},{"id":271821,"name":"Jing Zhang","orcid":"0000-0003-1194-0666","position":9,"is_corresponding":false},{"id":289854,"name":"Ryan M. O’Connell","orcid":"0000-0003-0860-1401","position":10,"is_corresponding":false},{"id":623398,"name":"Vinodh Pillai","orcid":"0000-0001-7126-6226","position":11,"is_corresponding":false},{"id":305764,"name":"Elizabeth O. Hexner","orcid":"0000-0002-1125-4060","position":12,"is_corresponding":false},{"id":251203,"name":"Mark R. Philips","orcid":"0000-0002-1179-8156","position":13,"is_corresponding":false},{"id":227839,"name":"Wei Tong","orcid":"0000-0001-9951-2273","position":14,"is_corresponding":false},{"id":636972,"name":"Jian‐Gang Ren","orcid":"0000-0002-1882-1865","position":0,"is_corresponding":true}],"reference_count":65,"raw_metadata":null,"created_at":"2026-07-19T01:07:27.434133Z","pmid":"37317963","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}