Overexpression of IL-1 receptor accessory protein in stem and progenitor cells and outcome correlation in AML and MDS

Abstract

IntroductionAcute myeloid leukemia (AML) and myelodysplastic syndromes (MDSs) are heterogeneous neoplastic diseases, and most subtypes have poor clinical outcomes. Despite the established use of poly-chemotherapy and the development of new agents that transiently reduce the tumor burden, relapse or failure to achieve durable remission continues to be the most common causes of death in most subtypes of AML and MDS. Recent experimental evidence suggests that AML arises from transformed immature hematopoietic cells after the accumulation of multiple stepwise genetic and epigenetic changes in hematopoietic stem cells (HSCs) and committed progenitors. 1 The series of transforming events are thought to initially give rise to preleukemia stem cells (pre-LSCs), preceding the formation of fully transformed LSCs. Defining the characteristics of LSCs, and also of pre-LSCs, is critical to understanding the genesis of leukemia and to developing strategies by which these cells can be eradicated. AML is characterized by a cellular heterogeneous tumor bulk, with LSCs at the top of the hierarchy and a differentiation block at various stages during myeloid maturation. 2 To address the problem of cellular heterogeneity within the tumor and to identify relevant molecular pathways effective in LSCs and pre-LSCs, novel experimental approaches other than the examination of bulk tumor cells need to be established. Recent findings have suggested that human LSCs are contained within different phenotypic compartments and at relatively low frequencies. [3][4][5] Several surface molecules were reported to permit enrichment of LSCs in AML. 4,[6][7][8][9][10][11] However, reliable markers for human LSCs at the single-cell level have yet to be identified; and because of the challenges associated with the use of xenograft models, the search for such markers remains difficult. Moreover, although there is clear evidence for the involvement of HSCs in AML pathogenesis, studies from murine models suggest that fully transformed and transplantable LSCs may reside at a committed progenitor stage. 12-15 Here we applied a novel approach of parallel transcriptional analysis of multiple, highly fractionated stem and progenitor populations in individual patients. We isolated phenotypic long-term HSCs (LT-HSCs), short-term HSCs (ST-HSCs), The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on May 11, 2018. by guest www.bloodjournal.org From and committed granulocyte-monocyte progenitors (GMP) from individual patients with AML, and compared gene expression profiles of each population with their phenotypic counterparts from age-matched healthy controls (HCs). Subsequent intersection of differentially expressed genes in the different cellular compartments allowed us to identify candidate genes that are consistently...

IL8-CXCR2 pathway inhibition as a therapeutic strategy against MDS and AML stem cells

“…GSE35008 and GSE35010). Gene Set Enrichment Analysis was performed by comparing the CXCR2 high signature to 2 published preleukemic HSC signatures (GSE35008 10 and GSE30377 4 ).…”

“…Recently, there have been increasing efforts to identify molecular aberrations that could serve as pharmacologic targets within AML and MDS stem cell compartments. [10][11][12][13][14][15][16] Resulting therapies have shown promising effects in preclinical studies, 17,18 but further work will be necessary to identify therapeutic targets against preleukemic stem cells that would lead to long-term remission and prevention of relapse in AML and MDS.…”

“…10 Briefly, mononuclear cells were isolated from bone marrow aspirates and peripheral blood samples by density gradient centrifugation and then subjected to immunomagnetic enrichment of CD34 1 cells (MiltenyiBiotec …”

Antibodies targeting human IL1RAP (IL1R3) show therapeutic effects in xenograft models of acute myeloid leukemia

“…Nonspecific binding of a therapeutic antibody may lead to serious adverse effects. IL1RAP is expressed on candidate AML stem cells, but not on corresponding normal hematopoietic stem cells (9,10). Among normal blood cells, IL1RAP is expressed mainly on monocytes, and AML cells are more sensitive than corresponding normal BM cells to ADCC induced by IL1RAP-targeting antibodies (8,9).…”

“…In a recent study, we showed that IL1RAP is expressed on the cell surface in ∼80% of AML patients and that candidate CD34 + CD38 − AML stem cells can be selectively killed in vitro by antibody-dependent cellular cytotoxicity (ADCC) (9). Furthermore, IL1RAP is upregulated on immature cells in high-risk AML with chromosome 7 aberrations, and increased IL1RAP expression correlates with poor prognosis (10). These findings could suggest IL1RAP as a novel and specific target for an antibody-based therapy in AML; however, in vivo evidences for therapeutic effects of IL1RAP targeting are lacking.…”