scholarly journals Siglec-15 Is a Novel Immunomodulatory Protein and Therapeutic Target in Childhood Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 6-7
Author(s):  
Claire E. Pillsbury ◽  
Jairo A. Fonseca ◽  
Jodi Dougan ◽  
Hasan Abukharma ◽  
Linda N. Liu ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Healthy Donor ◽  
Childhood Leukemia ◽  
Lymphoblastic Leukemia ◽  
B Cell Lymphoma ◽  
Myelogenous Leukemia ◽  
Soluble Form ◽  
Pediatric Leukemia ◽  
Cell Acute Lymphoblastic Leukemia

Despite advances that have greatly improved the overall survival of pediatric B cell acute lymphoblastic leukemia (B-ALL), it remains one of the leading causes of cancer-related death in children. Immunotherapy has shown efficacy in treatment of refractory disease, highlighting the need for greater understanding of the immune evasion mechanisms underlying this disease so that additional immune modulating therapeutic strategies can be developed. Siglec-15 (Sig15) was recently reported to have immune modulatory functions in the context of solid tumors. We have found that SIGLEC15 is overexpressed at the RNA level in primary B cell acute lymphoblastic leukemia (B-ALL), acute myelogenous leukemia (AML), and diffuse large B cell lymphoma as compared to healthy donor controls. As compared to healthy donor PBMCs, we have confirmed higher expression of Sig15 at the RNA and protein levels through RT-qPCR, immunoblotting, and flow cytometry across a panel of human B-ALL, AML, DLBCL, and T cell acute lymphoblastic leukemia (T-ALL) cell lines. Knockout of Sig15 expression in a BCR-ABL1+ murine model of B-ALL engrafted in immunocompetent and Rag1-/- immunodeficient recipients resulted in leukemia clearance in immunocompetent, but not immunodeficient, recipients and 100% survival (Figure 1). These data suggest a prominent role for Sig15 in the suppression of adaptive immune response to B-ALL as well as other hematological malignancies. Additional studies suggest that SIGLEC15 expression is positively regulated by NFκB signaling, which is known to be constitutively activated in certain B-ALL subsets. Importantly, we have observed release of a soluble form of Sig15 (sSig15) from B-ALL cells, which is regulated by PKC and calcineurin-mediated signaling. To discover translational application, we measured sSig15 in the plasma of both healthy and pediatric leukemia patients and found significantly higher levels of sSig15 as compared to healthy individuals (Figure 2; LLD = 5 pg/ml; **P<0.01). Together, these results suggest Siglec-15 is a novel and potent immunosuppressive molecule active in leukemia that may be targeted therapeutically to activate lymphocytes against leukemia cells. Disclosures Abukharma: NextCure, Inc.: Current Employment. Liu:NextCure, Inc.: Current Employment.

scholarly journals Siglec-15 Is a Novel Immunomodulatory Protein and Therapeutic Target in Acute Lymphoblastic Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 515-515
Author(s):  
Claire E. Pillsbury ◽  
Jairo A. Fonseca ◽  
Jodi Dougan ◽  
Hasan Abukharma ◽  
Gloria Gonzalez-Flamenco ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Immune Response ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
B Cell ◽  
Healthy Donor ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cells ◽  
Soluble Form ◽  
Cell Acute Lymphoblastic Leukemia

Abstract Immunotherapies have recently shown efficacy in treatment of aggressive, refractory pediatric B cell acute lymphoblastic leukemia (B-ALL), which remains one of the leading causes of cancer-related death in children. The immune evasion mechanisms of B-ALL are still being explored to discover new therapeutic targets and improve patient outcomes. Recent reports have implicated a role for the molecule Siglec-15 (Sig15) in regulating immune response in solid tumor-infiltrating macrophages. Our lab has found higher expression of SIGLEC15 at the RNA level in primary pediatric B-ALL as compared to healthy donor controls, as well as at the RNA and protein levels across a panel of B-ALL, T cell acute lymphoblastic leukemia (T-ALL), and diffuse large B cell lymphoma (DLBCL) cell lines compared to healthy donor PBMCs. Higher expression of SIGLEC15 in pediatric B-ALL samples from the TARGET database correlates with markers of PKC and NFκB activation known to drive B-ALL leukemogenesis, which we have demonstrated to regulate Sig15 RNA and protein expression in vitro. Knockout of Siglec15 expression in a BCR-ABL1 + murine model of B-ALL engrafted in immunocompetent and Rag1 -/- immunodeficient recipients resulted in leukemia clearance in immunocompetent, but not immunodeficient, recipients and 100% survival (Figure A, p=0.01 Sig15 KO into WT vs. Rag1 -/-). Further study indicates that Siglec15 expression on these leukemia cells suppresses T cell effector and memory population expansion at 7 days post-engraftment (Figure B) and correlates with higher levels of IL-10 and lower levels of CCL17 present in the bone marrow, representing a more immunosuppressive bone marrow milieu. These data suggest a prominent role for Sig15 in the suppression of adaptive immune response to B-ALL as well as other hematological malignancies. We have also reported for the first time the release of a soluble form of Sig15 (sSig15), which we have demonstrated to circulate at higher levels in the plasma of pediatric B-ALL patients compared to healthy donors (Figure C, ****P≤0.0001). Detection of this sSig15 negatively correlated with circulating levels of IL-12 and IL-1α/β (Figure D, depicting correlations of cytokines using Pearson's r), suggesting sSig15 levels correspond to a systemically immunosuppressive phenotype. Flow cytometry of fresh pediatric B ALL cells demonstrates expression of surface Sig15 in a subset of cases. Thus, Sig15 has the capacity to promote immunosuppressive effects at both marrow-localized and systemic levels. Together, these results suggest Siglec-15 is a novel, potent immunosuppressive molecule active in leukemia progression that may be targeted therapeutically to activate T lymphocytes against leukemia cells. Figure 1 Figure 1. Disclosures Abukharma: NextCure Inc.: Current Employment. Liu: NextCure: Current Employment, Current holder of stock options in a privately-held company.

scholarly journals Outcome of children with multiply relapsed B-cell acute lymphoblastic leukemia: a therapeutic advances in childhood leukemia & lymphoma study

Leukemia ◽  
2018 ◽  
Vol 32 (11) ◽  
pp. 2316-2325 ◽  
Author(s):  
Weili Sun ◽  
Jemily Malvar ◽  
Richard Sposto ◽  
Anupam Verma ◽  
Jennifer J. Wilkes ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Childhood Leukemia ◽  
Lymphoblastic Leukemia ◽  
Cell Acute Lymphoblastic Leukemia

scholarly journals Casitas B-cell lymphoma mutation in childhood T-cell acute lymphoblastic leukemia

2012 ◽  
Vol 36 (8) ◽  
pp. 1009-1015 ◽  
Author(s):  
Yuka Saito ◽  
Yoko Aoki ◽  
Hideki Muramatsu ◽  
Hideki Makishima ◽  
Jaroslaw P. Maciejewski ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
B Cell ◽  
Cell Lymphoma ◽  
Lymphoblastic Leukemia ◽  
B Cell Lymphoma ◽  
Cell Acute Lymphoblastic Leukemia

scholarly journals Single cell mRNA signals reveal a distinct developmental state of KMT2A-rearranged infant B-cell acute lymphoblastic leukemia

2021 ◽  
Author(s):  
Eleonora Khabirova ◽  
Laura Jardine ◽  
Tim Coorens ◽  
Simone Webb ◽  
Taryn Treger ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Childhood Leukemia ◽  
Lymphoblastic Leukemia ◽  
Meta Analysis ◽  
Developmental State ◽  
Gene Fusions ◽  
The Core ◽  
Increasing Trend ◽  
Cell Acute Lymphoblastic Leukemia

Infant B-cell acute lymphoblastic leukemia (B-ALL) has not followed the increasing trend towards cure seen in other childhood B-ALLs. The prognosis for infants with KMT2A gene fusions is especially poor, and the origins of this aggressive leukemia remain unknown. Here, we investigated the developmental state of KMT2A-rearranged infant B-ALL within hematopoietic hierarchies of human fetal bone marrow, using bulk mRNA meta-analysis of childhood leukemia and examination of single lymphoblast transcriptomes. KMT2A-rearranged infant B-ALL was uniquely dominated by an early lymphocyte precursor (ELP) state. Direct comparison of infant lymphoblasts with ELP cells distilled the core oncogenic transcriptome of cancer cells which harboured potentially targetable hybrid myeloid-lymphoid features. Overall our quantitative molecular analyses demonstrate a distinct developmental state of KMT2A-rearranged infant B-ALL.

scholarly journals Elevated Levels of Interleukin-9 in Obese Microenvironments Promote Leukemia Progression and Chemoresistance in B-Cell Acute Lymphoblastic Leukemia Cells

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1468-1468
Author(s):  
Jamie A.G. Hamilton ◽  
Miyoung Lee ◽  
Ganesh R Talekar ◽  
Curtis J. Henry
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Pediatric Patients ◽  
Lymphoblastic Leukemia ◽  
B Cell Lymphoma ◽  
Obese Patients ◽  
Obese Mice ◽  
Survival Pathways ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Interleukin 9

Background: The CDC reports that obesity rates in children and adolescents have more than tripled since the 1970's (Ogden et al., 2006; Ogden et al., 2016). Obese pediatric patients with B-cell acute lymphoblastic leukemia (B-ALL) have inferior overall survival compared to lean patients, with obese patients having a 2.5-fold increased risk of an adverse event and an almost 4-fold greater risk of death compared to non-obese patients (Butturini et al., 2007; Eissa et al., 2017; Ethier et al., 2012). Emerging data suggest that factors in the obese microenvironment directly promote chemoresistance in B-ALL cells (Ehsanipour et al., 2013; Sheng et al., 2016). Despite the emerging epidemiological and clinical studies highlighting the negative impact of obesity on cancer outcomes, there remains a lack of understanding of the molecular mechanisms underlying the dismal outcomes of obese patients with B-ALL. Methods: Using a global cytokine profiling array, we found that multiple cytokines were secreted at low levels in a lean microenvironment compared to the obese microenvironment. We decided to focus solely on cytokines exclusively present at high concentrations in the obese microenvironment relative to the lean microenvironment in order to determine their impact on the function of murine and human B-ALL cell lines. We also utilized the diet-induced murine model of obesity to determine how survival and treatment outcomes differ in lean and obese mice challenged with B-ALL. Furthermore, we determined how obesity altered the function of B-ALL cells in pediatric patients using primary samples obtained through the Aflac Leukemia and Lymphoma Biorepository. Results: We made the novel finding that Interleukin-9 is elevated in obese microenvironments and alters the function of human B-ALL cells. It has been previously shown that interleukin-9 (IL-9) promotes chemoresistance in diffuse large B-cell lymphoma and is associated with a worse prognosis in patients with B-cell chronic lymphocytic leukemia (Chen, Lv, Li, Lu, & Wang, 2014; Lv, Feng, Ge, Lu, & Wang, 2016); however, the impact of IL-9 on B-ALL development is unknown. We have found that IL-9 levels were significantly increased in adipose-rich microenvironments. Human B-ALL cells exposed to these environments upregulated the IL-9 receptor (IL-9R), which was not observed in stromal-cell rich microenvironments. Stimulating human B-ALL cells with recombinant IL-9 (rIL-9) promoted cell progression and extensive proliferation over 3 days of culture. Furthermore, rIL-9 stimulation of human B-ALL cells activated survival pathways (STAT3) which coincides with the induction of chemoresistance to methotrexate. Conclusions: We have found that IL-9 levels are elevated in obese microenvironments and alters the function of human B-ALL (increased proliferation, activation of survival pathways, and induction of chemoresistance). In ongoing murine studies, we will determine if the survival of obese mice with B-ALL is prolonged when chemotherapy treatment and IL-9 neutralizing strategies are combined. Disclosures No relevant conflicts of interest to declare.

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