Class II-associated invariant chain peptide as predictive immune marker in minimal residual disease in acute myeloid leukemia.

The majority of patients with acute myeloid leukemia (AML) reach complete remission after high-dose chemotherapy. Still, half of these patients experience a relapse due to presence of minimal residual disease (MRD). Here we discuss the poor prognostic role of class II-associated invariant chain peptide (CLIP) expression on residual leukemic cells.

High class II-associated invariant chain peptide expression on residual leukemic cells is associated with increased relapse risk in acute myeloid leukemia.

The presence of class II-associated invariant chain (CLIP) on leukemic cells is negatively associated with clinical outcome in untreated acute myeloid leukemia (AML). CLIP plays a role in the immune escape of leukemic cells, suggesting that it impairs the immunogenicity of minimal residual disease (MRD) cells causing a relapse. Here, we demonstrate that CLIP expression on leukemia-associated phenotype (LAP)-positive cells during follow-up is significantly correlated with a shortened relapse-free survival, even in those patients who are generally considered as MRD(low) (0.

Tumor heterogeneity makes AML a "moving target" for detection of residual disease.

Detection of minimal residual disease is recognized as an important post-therapy risk factor in acute myeloid leukemia patients. Two most commonly used methods for residual disease monitoring are real-time quantitative polymerase chain reaction and multiparameter flow cytometry. The results so far are very promising, whereby it is likely that minimal residual disease results will enable to guide future post-remission treatment strategies.

Tumor heterogeneity makes AML a "moving target" for detection of residual disease.

Detection of minimal residual disease is recognized as an important post-therapy risk factor in acute myeloid leukemia patients. Two most commonly used methods for residual disease monitoring are real time quantitative polymerase chain reaction and multiparameter flow cytometry. Results so far are very promising, whereby it is likely that minimal residual disease results will enable to guide future post-remission treatment strategies.

Tumor immune escape in acute myeloid leukemia: Class II-associated invariant chain peptide expression as result of deficient antigen presentation.

In this overview, we discuss the role of class II-associated invariant chain peptide (CLIP) in acute myeloid leukemia (AML), one of the few tumors expressing HLA class II. The clinical impact, function and regulation of CLIP expression on leukemic cells is addressed, indicating its potential as immunotherapeutic target in AML.

Promiscuous binding of invariant chain-derived CLIP peptide to distinct HLA-I molecules revealed in leukemic cells.

Antigen presentation by HLA class I (HLA-I) and HLA class II (HLA-II) complexes is achieved by proteins that are specific for their respective processing pathway. The invariant chain (Ii)-derived peptide CLIP is required for HLA-II-mediated antigen presentation by stabilizing HLA-II molecules before antigen loading through transient and promiscuous binding to different HLA-II peptide grooves. Here, we demonstrate alternative binding of CLIP to surface HLA-I molecules on leukemic cells.

Inactivating PSMB5 mutations and P-glycoprotein (multidrug resistance-associated protein/ATP-binding cassette B1) mediate resistance to proteasome inhibitors: ex vivo efficacy of (immuno)proteasome inhibitors in mononuclear blood cells from patients with rheumatoid arthritis.

Bortezomib (BTZ), a registered proteasome inhibitor (PI) for multiple myeloma, has also been proposed as a potential antirheumatic agent. Its reported side effects, however, make it unappealing for long-term administration, and resistance may also develop. To overcome this, second-generation PIs became available.

Class II-associated invariant chain peptide expression represents a novel parameter for flow cytometric detection of acute promyelocytic leukemia.

Because of severe bleeding complications, patients with acute promyelocytic leukemia (APL) have to be treated with all-trans retinoic acid immediately following diagnosis. In addition to morphology, flow cytometry contributes to a rapid detection of APL according to phenotypic characteristics of leukemic cells. In some patients, these analyses are inconclusive or even contradictory to diagnosis.

Role of immune responses in the pathogenesis of low-risk MDS and high-risk MDS: implications for immunotherapy.

The myelodysplastic syndromes (MDS) constitute a group of heterogeneous clonal haemopoietic stem cell disorders, characterized by ineffective and dysplastic haematopoiesis with varying degrees of peripheral cytopenia. Low-risk MDS is characterized by increased apoptosis in the bone marrow (BM) with autoimmune characteristics whereas the advanced or high-risk stages involve immune evasion and secondary DNA damage, giving cells growth potential to progress into acute myeloid leukaemia (AML). Nevertheless, the causes of MDS remain poorly defined and it is not clear how the disease progresses from an early stage to advanced MDS and AML.

Absence of class II-associated invariant chain peptide on leukemic blasts of patients promotes activation of autologous leukemia-reactive CD4+ T cells.

Immune escape in cancer poses a substantial obstacle to successful cancer immunotherapy. Multiple defects in HLA class I antigen presentation exist in cancer that may contribute to immune escape, but less is known about roles for HLA class II antigen presentation. On class II(+) leukemic blasts, the presence of class II-associated invariant chain peptide (CLIP) is known to be correlated with poor survival in acute myeloid leukemia (AML).

Targeting Toll-like receptor 7/8 enhances uptake of apoptotic leukemic cells by monocyte-derived dendritic cells but interferes with subsequent cytokine-induced maturation.

Therapeutic vaccination with dendritic cells (DC) is an emerging investigational therapy for eradication of minimal residual disease in acute myeloid leukemia. Various strategies are being explored in manufacturing DC vaccines ex vivo, e.g.

Alternative Ii-independent antigen-processing pathway in leukemic blasts involves TAP-dependent peptide loading of HLA class II complexes.

During HLA class II synthesis in antigen-presenting cells, the invariant chain (Ii) not only stabilizes HLA class II complexes in the endoplasmic reticulum, but also mediates their transport to specialized lysosomal antigen-loading compartments termed MIICs. This study explores an alternative HLA class II presentation pathway in leukemic blasts that involves proteasome and transporter associated with antigen processing (TAP)-dependent peptide loading. Although HLA-DR did associate with Ii, Ii silencing in the human class II-associated invariant chain peptide (CLIP)-negative KG-1 myeloid leukemic cell line did not affect total and plasma membrane expression levels of HLA-DR, as determined by western blotting and flow cytometry.

Class II-associated invariant chain peptide down-modulation enhances the immunogenicity of myeloid leukemic blasts resulting in increased CD4+ T-cell responses.

Background: Disease recurrence in patients with acute myeloid leukemia may be partially explained by the escape of leukemic blasts from CD4(+) T-cell recognition. The current study investigates the role of aberrant HLA class II antigen presentation on leukemic blasts by determining both the clinical and functional impact of the class II-associated invariant chain peptide (CLIP).

Design And Methods: The levels of expression of CLIP and HLA-DR on blood and bone marrow samples from 207 patients with acute myeloid leukemia were correlated with clinical outcome.

Interleukin-2 receptor alpha-chain (CD25) expression on leukaemic blasts is predictive for outcome and level of residual disease in AML.

We investigated the role of CD25 as a prognostic marker in acute myeloid leukaemia (AML). Seventy-two newly diagnosed patients < or =60 years were retrospectively analysed by flow cytometry for CD25 positivity of AML blasts. Patients with CD25 expression of >10%, when compared to < or =10%, had a significantly shorter overall survival (OS, p=0.

Identification of distinct prognostic subgroups in low- and intermediate-1-risk myelodysplastic syndromes by flow cytometry.

The World Health Organization (WHO) classification contributes to refined classification and prognostication of myelodysplastic syndromes (MDSs). Flow cytometry might add significantly to diagnostic and prognostic criteria. Our analysis of bone marrow samples from 50 patients with MDS showed aberrant expression of differentiation antigens in the myelomonocytic lineage.

Sulfasalazine sensitises human monocytic/macrophage cells for glucocorticoids by upregulation of glucocorticoid receptor alpha and glucocorticoid induced apoptosis.

Background: Glucocorticoids (GCs) are commonly used in the treatment of (chronic) inflammatory diseases and cancer, but inherent or acquired resistance to these drugs limits their optimal efficacy. The availability of drugs that could modulate GC resistance is therefore of potential clinical interest.

Objective: To explore the molecular basis of GC sensitisation of GC resistant monocytic/macrophage cells after chronic exposure to sulfasalazine.