title: Tetraspanin CD82 regulates bone marrow homing of acute myeloid leukemia by modulating the molecular organization of N-cadherin.
abstract: Communication between acute myeloid leukemia (AML) and the bone marrow microenvironment is known to control disease progression. Therefore, regulation of AML cell trafficking and adhesion to the bone marrow is of significant interest. In this study, we demonstrate that differential expression of the membrane scaffold CD82 modulates the bone marrow homing of AML cells. By combining mutational analysis and super-resolution imaging, we identify membrane protein clustering by CD82 as a regulator of AML cell adhesion and bone marrow homing. Cluster analysis of super-resolution data indicates that N-linked glycosylation and palmitoylation of CD82 are both critical modifications that control the microdomain organization of CD82 as well as the nanoscale clustering of associated adhesion protein, N-cadherin. We demonstrate that the inhibition of CD82 glycosylation increases the molecular packing of N-cadherin and promotes the bone marrow homing of AML cells. In contrast, we find that the inhibition of CD82 palmitoylation disrupts the formation and organization of N-cadherin clusters and significantly diminishes bone marrow trafficking of AML. Taken together, these data establish a mechanism where the membrane organization of CD82, through specific posttranslational modifications, regulates N-cadherin clustering and membrane density, which impacts the in vivo trafficking of AML cells. As such, these observations provide an alternative model for targeting AML where modulation of protein organization within the membrane may be an effective treatment therapy to disrupt the bone marrow homing potential of AML cells.
authors.affiliation: Department of Pathology, University of New Mexico Health Sciences Center, University of New Mexico, Albuquerque, NM, USA.
authors.forename: K D
authors.initials: KD
authors.lastname: Marjon
authors.affiliation: Department of Pathology, University of New Mexico Health Sciences Center, University of New Mexico, Albuquerque, NM, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Termini
authors.affiliation: Department of Pathology, University of New Mexico Health Sciences Center, University of New Mexico, Albuquerque, NM, USA.
authors.forename: K L
authors.initials: KL
authors.lastname: Karlen
authors.affiliation: Department of Pathology, University of New Mexico Health Sciences Center, University of New Mexico, Albuquerque, NM, USA.
authors.forename: C
authors.initials: C
authors.lastname: Saito-Reis
authors.affiliation: Department of Pathology, University of New Mexico Health Sciences Center, University of New Mexico, Albuquerque, NM, USA.
authors.forename: C E
authors.initials: CE
authors.lastname: Soria
authors.affiliation: Department of Physics and Astronomy, University of New Mexico, Albuquerque, NM, USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Lidke
authors.affiliation: Department of Pathology, University of New Mexico Health Sciences Center, University of New Mexico, Albuquerque, NM, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Gillette
mesh_terms: D015703:Antigens, CD / Q000737:chemistry*; D001853:Bone Marrow / Q000502:physiology*; D015820:Cadherins / Q000737:chemistry*; D002448:Cell Adhesion; D006031:Glycosylation; D006801:Humans; D051861:Kangai-1 Protein / Q000502:physiology*; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D054878:Lipoylation; D011499:Protein Processing, Post-Translational; D019718:Receptors, CXCR4 / Q000502:physiology
chemical_list: D015703:Antigens, CD; C497688:CD82 protein, human; C050361:CDH2 protein, human; C527276:CXCR4 protein, human; D015820:Cadherins; D051861:Kangai-1 Protein; D019718:Receptors, CXCR4