RAB27B controls palmitoylation-dependent NRAS trafficking and signaling in myeloid leukemia.
Jian-Gang Ren, Bowen Xing, Kaosheng Lv, Rachel A O'Keefe, Mengfang Wu, Ruoxing Wang, Kaylyn M Bauer, Arevik Ghazaryan, George M Burslem, Jing Zhang, Ryan M O'Connell, Vinodh Pillai, Elizabeth O Hexner, Mark R Philips, Wei Tong
Author Information
Jian-Gang Ren: The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine, Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, Hubei, China.
Bowen Xing: Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Kaosheng Lv: Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Rachel A O'Keefe: Department of Medicine and Perlmutter Cancer Center, New York University Grossman School of Medicine, New York, New York, USA.
Mengfang Wu: Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Ruoxing Wang: Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Kaylyn M Bauer: Department of Pathology, University of Utah, Salt Lake City, Utah, USA.
Arevik Ghazaryan: Department of Pathology, University of Utah, Salt Lake City, Utah, USA.
George M Burslem: Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Jing Zhang: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Ryan M O'Connell: Department of Pathology, University of Utah, Salt Lake City, Utah, USA.
Vinodh Pillai: Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Elizabeth O Hexner: Division of Hematology and Oncology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Mark R Philips: Department of Medicine and Perlmutter Cancer Center, New York University Grossman School of Medicine, New York, New York, USA.
Wei Tong: Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
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.
