LRRC25 plays a key role in all-trans retinoic acid-induced granulocytic differentiation as a novel potential leukocyte differentiation antigen

Abstract

Leukocyte differentiation antigens (LDAs) play important roles in the immune system, by serving as surface markers and participating in multiple biological activities, such as recognizing pathogens, mediating membrane signals, interacting with other cells or systems, and regulating cell differentiation and activation. Data mining is a powerful tool used to identify novel LDAs from whole genome. LRRC25 (leucine rich repeat-containing 25) was predicted to have a role in the function of myeloid cells by a large-scale “omics” data analysis. Further experimental validation showed that LRRC25 is highly expressed in primary myeloid cells, such as granulocytes and monocytes, and lowly/intermediately expressed in B cells, but not in T cells and almost all NK cells. It was down-regulated in multiple acute myeloid leukemia (AML) cell lines and bone marrow cells of AML patients and up-regulated after all-trans retinoic acid (ATRA)-mediated granulocytic differentiation in AML cell lines and acute promyelocytic leukemia (APL; AML-M3, FAB classification) cells. Localization analysis showed that LRRC25 is a type I transmembrane molecule. Although ectopic LRRC25 did not promote spontaneous differentiation of NB4 cells, knockdown of LRRC25 by siRNA or shRNA and knockout of LRRC25 by the CRISPR-Cas9 system attenuated ATRA-induced terminal granulocytic differentiation, and restoration of LRRC25 in knockout cells could rescue ATRA-induced granulocytic differentiation. Therefore, LRRC25, a potential leukocyte differentiation antigen, is a key regulator of ATRA-induced granulocytic differentiation.Electronic supplementary materialThe online version of this article (doi:10.1007/s13238-017-0421-7) contains supplementary material, which is available to authorized users.

Complex polymorphisms in endocytosis genes suggest alpha-cyclodextrin as a treatment for breast cancer

“…A third meta-analysis [ 79 ] based the above three and eleven other U4C data sets,[ 80 ] identified five novel breast cancer genes, three with nuclear function ( RCCD1 , ANKL1 , DHODH [ 81 ]); ACAP1 and LRRC25 were hypothesized to be involved in cell proliferation (activating Arf6 protein) and inflammatory response (activating hematopoietic cells), respectively, [ 79 ] In fact, both genes are can be related to EEC/PI in metastases: ACAP1 ( Fig 3 , top right) regulates recycling of integrin β1 during cell migration [ 82 ]; LRRC25 , which regulates development of neutrophils needed for metastases,[ 83 ] carries a PI3K interaction motive. [ 84 ]…”

Prioritizing risk genes as novel stratification biomarkers for acute monocytic leukemia by integrative analysis

“…The role of LCP1 and HCK in leukemia or lymphoma has been sporadically reported [23][24][25][26]. However, role of LRRC25, NCF2 and RAB31 is largely unknown and the experimental validation are demanded in future study to facilitate these proteins used in clinic [34][35][36][37][38]. As an initial verification, we have validated that the high expression of four genes is associated with Venetoclax drug resistance at pooled cell level of PB in Beat_AML corhot and also at single cell level in the longitudinal relapsed BM sample of a M5 patient (Fig.…”

Blood cell traits’ GWAS loci colocalization with variation in PU.1 genomic occupancy prioritizes causal noncoding regulatory variants

“…LRRC25 , also called monocyte and plasmacytoid-activated protein (MAPA), is a gene necessary for differentiation of granulocytes, which share lineages with monocytes. 62 At this locus, we found that the PU.1 bQTL signal showed significant colocalization with monocyte count and percentage, neutrophil count and percentage, and white blood cell count association signals 8 , 32 (JLIM p = 5 × 10 −5 , 4 × 10 −5 , 1 × 10 −5 , 1 × 10 −5 , and 1 × 10 −5 , respectively, and Coloc PP[colocalization] = 0.99, 0.99, 0.99, 0.99, and 0.98, respectively; Figures 6 A and S6 A; Table S4 ). As the association Z scores show, variants significantly associated with lower PU.1 binding are also associated with a lower monocyte percentage, consistent with colocalization ( Figure 6 A).…”