Leukocyte immunoglobulin-like receptor B4(LILRB4)is an inhibitory receptor in the LILR family mainly expressed on normal and malignant human cells of myeloid origin.By binding to ligands,LILRB4 is activated and subseq...Leukocyte immunoglobulin-like receptor B4(LILRB4)is an inhibitory receptor in the LILR family mainly expressed on normal and malignant human cells of myeloid origin.By binding to ligands,LILRB4 is activated and subsequently recruits adaptors to cytoplasmic immunoreceptor tyrosine inhibitory motifs to initiate different signaling cascades,thus playing an important role in physiological and pathological conditions,including autoimmune diseases,microbial infections,and cancers.In normal myeloid cells,LILRB4 regulates intrinsic cell activation and differentiation.In disease-associated or malignant myeloid cells,LILRB4 is significantly correlated with disease severity or patient survival and suppresses T cells,thereby participating in the pathogenesis of various diseases.In summary,LILRB4 functions as an immune checkpoint on myeloid cells and may be a promising therapeutic target for various human immune diseases,especially for cancer immunotherapy.展开更多
We recently demonstrated that leukocyte Ig-like receptor 4(LILRB4)expressed by monocytic acute myeloid leukemia(AML)cells mediates T-cell inhibition and leukemia cell infiltration via its intracellular domain.The cyto...We recently demonstrated that leukocyte Ig-like receptor 4(LILRB4)expressed by monocytic acute myeloid leukemia(AML)cells mediates T-cell inhibition and leukemia cell infiltration via its intracellular domain.The cytoplasmic domain of LILRB4 contains three immunoreceptor tyrosine-based inhibitory motifs(ITIMs);the tyrosines at positions 360,412,and 442 are phosphorylation sites.Here,we analyzed how the ITIMs of LILRB4 in AML cells mediate its function.Our in vitro and in vivo data show that Y412 and Y442,but not Y360,of LILRB4 are required for T-cell inhibition,and all three ITIMs are needed for leukemia cell infiltration.We constructed chimeric proteins containing the extracellular domain of LILRB4 and the intracellular domain of LILRB1 and vice versa.The intracellular domain of LILRB4,but not that of LILRB1,mediates T-cell suppression and AML cell migration.Our studies thus defined the unique signaling roles of LILRB4 ITIMs in AML cells.展开更多
Objective Chronic myelomonocytic leukemia(CMML) has been categorized as an uncommon hematological malignancy with overlapping features of myelodysplastic syndromes(MDS) and myeloproliferative neoplasms that have an in...Objective Chronic myelomonocytic leukemia(CMML) has been categorized as an uncommon hematological malignancy with overlapping features of myelodysplastic syndromes(MDS) and myeloproliferative neoplasms that have an inherent risk of progressing to acute myeloid leukemia(AML). Methods This study presents a case of confirmed CMML combined with M protein, in which the molecular changes upon progression to AML and under decitabine(DAC) plus bortezomib therapy were reported by tracking variant allele frequency(VAF) of mutations in a series of bone marrow samples. Results First, variable sensitivity of clones was observed during DAC treatment, and incomplete mutation clearance may be associated with low overall response rate and unsustained response. Secondly, DAC cannot prevent the new genetic alterations and accumulation of genetic progression on treatment, leading to acute transformation. Finally, autoimmunity was found to have acted as an important pathogenetic factor, increasing the additive mutations that further drive the clonal evolution in CMML. Conclusion Overall, changes in mutations and clonal architecture during CMML progression or treatment are predictive of an early evaluation of therapeutic strategies in CMML.展开更多
基金This work was supported by the Imported Scholar Project and Startup from Peking University Health Science Center(68263Y1056 to MD).
文摘Leukocyte immunoglobulin-like receptor B4(LILRB4)is an inhibitory receptor in the LILR family mainly expressed on normal and malignant human cells of myeloid origin.By binding to ligands,LILRB4 is activated and subsequently recruits adaptors to cytoplasmic immunoreceptor tyrosine inhibitory motifs to initiate different signaling cascades,thus playing an important role in physiological and pathological conditions,including autoimmune diseases,microbial infections,and cancers.In normal myeloid cells,LILRB4 regulates intrinsic cell activation and differentiation.In disease-associated or malignant myeloid cells,LILRB4 is significantly correlated with disease severity or patient survival and suppresses T cells,thereby participating in the pathogenesis of various diseases.In summary,LILRB4 functions as an immune checkpoint on myeloid cells and may be a promising therapeutic target for various human immune diseases,especially for cancer immunotherapy.
基金We thank the National Cancer Institute(1R01CA172268)the Cancer Prevention and Research Institute of Texas(RP180435)+3 种基金the Robert A.Welch Foundation(I-1834)China Natural Science Foundation(81872332)Shandong Natural Science Foundation(2018GSF118201)Yantai Science and Technology Development Plan(2018ZHGY070)for generous support.
文摘We recently demonstrated that leukocyte Ig-like receptor 4(LILRB4)expressed by monocytic acute myeloid leukemia(AML)cells mediates T-cell inhibition and leukemia cell infiltration via its intracellular domain.The cytoplasmic domain of LILRB4 contains three immunoreceptor tyrosine-based inhibitory motifs(ITIMs);the tyrosines at positions 360,412,and 442 are phosphorylation sites.Here,we analyzed how the ITIMs of LILRB4 in AML cells mediate its function.Our in vitro and in vivo data show that Y412 and Y442,but not Y360,of LILRB4 are required for T-cell inhibition,and all three ITIMs are needed for leukemia cell infiltration.We constructed chimeric proteins containing the extracellular domain of LILRB4 and the intracellular domain of LILRB1 and vice versa.The intracellular domain of LILRB4,but not that of LILRB1,mediates T-cell suppression and AML cell migration.Our studies thus defined the unique signaling roles of LILRB4 ITIMs in AML cells.
基金Supported by a grant from the Foundation of Ruijin Hospital North Affiliated with Shanghai Jiao Tong University School of Medicine(No.2018ZY03)
文摘Objective Chronic myelomonocytic leukemia(CMML) has been categorized as an uncommon hematological malignancy with overlapping features of myelodysplastic syndromes(MDS) and myeloproliferative neoplasms that have an inherent risk of progressing to acute myeloid leukemia(AML). Methods This study presents a case of confirmed CMML combined with M protein, in which the molecular changes upon progression to AML and under decitabine(DAC) plus bortezomib therapy were reported by tracking variant allele frequency(VAF) of mutations in a series of bone marrow samples. Results First, variable sensitivity of clones was observed during DAC treatment, and incomplete mutation clearance may be associated with low overall response rate and unsustained response. Secondly, DAC cannot prevent the new genetic alterations and accumulation of genetic progression on treatment, leading to acute transformation. Finally, autoimmunity was found to have acted as an important pathogenetic factor, increasing the additive mutations that further drive the clonal evolution in CMML. Conclusion Overall, changes in mutations and clonal architecture during CMML progression or treatment are predictive of an early evaluation of therapeutic strategies in CMML.
