In contrast, in low-risk patients, only CD200+ cells could engraft primary and secondary recipients, which demonstrated self-renewal ability

In contrast, in low-risk patients, only CD200+ cells could engraft primary and secondary recipients, which demonstrated self-renewal ability. SULF1 antibody TTI-CD200 in vitro and in vivo. Treating mice with established disease significantly reduced disease burden and extended survival. These findings demonstrate that CD200 could be an attractive target for treating low-risk ALL, with minimal off-tumor effects that beset current immunotherapeutic approaches. Introduction The risk of relapse remains high in pediatric acute lymphoblastic leukemia (ALL), particularly among teenagers and young adults.1,2 Despite the ongoing development CH5132799 of diagnostic and screening technologies, survival rates have remained largely unchanged using conventional therapies, with limited progress for children who do not respond to initial therapy.3 Assessment of measurable residual disease (MRD) levels is the most powerful means CH5132799 of predicting outcome in childhood ALL. Flow cytometry4,5 and, more recently, next-generation sequencing6-8 are increasingly replacing polymerase chain reaction (PCR) as methods of choice for MRD analyses. Next-generation sequencing is the most sensitive and has the CH5132799 advantage of providing more specific readouts of MRD than reverse transcriptase PCR (RT-PCR), and multiple rearrangements can be sequenced in a single run.9,10 Combining MRD analyses with genetic screening has further improved diagnosis, and risk stratification and can lead to better predictions of response.11 As a result of these advances, it has been possible to identify markers with altered expression in leukemia cells, which permits discrimination from normal hemopoietic cells. Altered expression of certain cell surface antigens and genes in leukemia has been exploited for therapeutic targeting: blinatumomab,12,13 chimeric antigen receptor (CAR) T-cell antigens against CD19,14,15 epratuzumab, and inotuzumab (anti-CD22)16-18 BCL-2 inhibitors. However, a limitation of such therapies is usually that they affect all cells that express the target antigens, not just leukemia cells. In addition, several studies have shown that some populations of leukemia cells that can establish the disease in murine models, termed leukemia-propagating cells (LPCs), lack expression of CD10, CD19, and CD2219-22 and thus will be unaffected by such therapies. This may be one reason why escape of CD19C cells remains a problem after treatment with CD19 CAR T cells.15,23,24 Consequently, there remains a need to identify new markers that could be used to further define leukemia-associated immunophenotypes. Genome-wide expression studies and phenotypic discovery platforms have helped to reveal markers related to leukemia-associated immunophenotypes that can be tracked CH5132799 during therapy and could be potential targets for therapy.25-27 CH5132799 Some markers that were overexpressed, such as CD34 and CD58,26,28 had been widely used in MRD analyses, but the addition of some new markers such as CD97 to flow cytometry MRD panels improved the discrimination of normal and leukemia cells.29 CD200 was identified as one of the top 10 10 differentially regulated genes.25 Interestingly, overexpression of CD200 has also been reported in acute myeloid leukemia (AML),26,28 chronic lymphocytic leukemia (CLL),29 and multiple myeloma.30 It has been associated with inferior outcomes in CLL and was identified as one of the most important therapeutic targets for this malignancy.27 In pediatric ALL, the relevance of these markers has not been investigated in a functional context, so their roles in leukemogenesis are not known. In this study, we explored whether expression of CD58, CD97, or CD200 was a characteristic of ALL cells with in vivo propagating ability and their potential as targets for therapy. Methods Samples The use of human samples was approved by London Brent Research Ethics Committee (12/LO/1193). Animal studies were conducted under license from the United Kingdom Home Office. This study was conducted in accordance with the Declaration of Helsinki. Bone marrow (BM) cells from children (median age, 4 years; range, 1-17 years) with B-cell precursor ALL (BCP-ALL) (n = 63) at diagnosis or relapse were collected with approval by University Hospitals Bristol and Weston National Health Service Foundation Trust. Patient characteristics are provided in Table 1. Patients from the UKALL 2003 trial were classed as low risk if leukemia cell levels were 0.01% and high risk if levels were 0.01% at day 29 of induction.31 In UKALL 2011, low risk represented.

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