CXorf48 is a potential therapeutic target for achieving treatment-free remission in CML patients

Abstract

Although the introduction of tyrosine kinase inhibitors (TKIs) has improved overall survival of patients with chronic myeloid leukemia (CML), about half of the patients eventually relapse after cessation of TKIs. In contrast, the remainder of the patients maintain molecular remission without TKIs, indicating that the patients’ immune system could control proliferation of TKI-resistant leukemic stem cells (LSCs). However, the precise mechanism of immunity against CML-LSCs is not fully understood. We have identified a novel immune target, CXorf48, expressed in LSCs of CML patients. Cytotoxic T cells (CTLs) induced by the epitope peptide derived from CXorf48 recognized CD34+CD38− cells obtained from the bone marrow of CML patients. We detected CXorf48-specific CTLs in the peripheral blood mononuclear cells from CML patients who have discontinued imatinib after maintaining complete molecular remission for more than 2 years. Significantly, the relapse rate of CXorf48-specific CTL-negative patients was 63.6%, compared to 0% in CXorf48-specific CTL-positive patients. These results indicate that CXorf48 could be a promising therapeutic target of LSCs for immunotherapy to obtain durable treatment-free remission in CML patients.

Characteristics of a Novel Target Antigen against Myeloma Cells for Immunotherapy

“…CXorf48 is a CTA that is expressed in chronic myelogenous leukaemia cells and not in normal blood cells [11]. This antigen is also detected in some of solid cancers including head and neck carcinoma [21].…”

“…CTAs located inside the cells are processed by the proteasome, modified by the endoplasmic reticulum and Golgi apparatus, moved to cell surface, and finally presented by the HLA molecule. We previously identified an epitope, CXorf48 [49][50][51][52][53][54][55][56][57] , which binds to HLA-A*24;02, the most popular HLA class I haplotype in the Japanese population [11]. PRAME, another CTA located in the 22 nd chromosome [24], was also strongly expressed in all myeloma cell lines, which is consistent with reports that gene expression levels are lower in X chromosomal genes compared to autosomal genes [25].…”

“…We detected low levels of CXorf48 protein expression in KMS11, which was consistent with the RT-qPCR results. Our previous study showed that the CXorf48 gene is not expressed in blood mononuclear cells or bone marrow mononuclear cells [11]. Therefore, CXorf48 can be a myeloma-specific antigen.…”

“…CXorf48 expression was detected using the standard reverse transcription polymerase chain reaction (RT-PCR) or quantitative PCR, as previously described [11]. Total RNA was extracted from cancer cell lines and peripheral blood mononuclear cells (PBMNC) from healthy donor (HD) using and reverse, 5'-TATTGAGAGGGTTTCCAAGGGGTT-3').…”

Cancer testis antigen 55 deficiency attenuates colitis-associated colorectal cancer by inhibiting NF-κB signaling

“…A recent study reported that CT55 is a potential novel immune target for achieving treatment-free remission in chronic myeloid leukemia patients 27 , which prompted us to investigate whether CT55 affects immune and inflammatory responses during the process of CAC. Analysis of the mechanisms by which CT55 mediates a significant effect on CAC revealed that TNF-α-induced NF-κB signaling is the major downstream target.…”