Expression of CD25 on leukemic stem cells in BCR-ABL1+ CML: Potential diagnostic value and functional implications

Sadovnik, Irina; Herrmann, Harald; Eisenwort, Gregor; Blatt, Katharina; Hoermann, Gregor; Mueller, Niklas; Sperr, Wolfgang R.; Valent, Peter

doi:10.1016/j.exphem.2017.04.003

Cited by 34 publications

(43 citation statements)

References 64 publications

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“…A number of surface markers have recently been identified on putative LSCs. [21][22][23][24][25][26][27][28][29][36][37][38][39]43,[46][47][48][49][50] We extended these analyses and compared the phenotype of AML LSCs and CML LSCs with each other and with the phenotype of HSCs and stem cells in other neoplasms. Although the LSC phenotype in CML was found to be unique and recurrent, the LSC phenotype in AML showed considerable heterogeneity without a definitive relationship to a morphologic or WHO type of AML.…”

Section: Discussionmentioning

confidence: 99%

Delineation of target expression profiles in CD34+/CD38− and CD34+/CD38+ stem and progenitor cells in AML and CML

Herrmann

Sadovnik²,

Eisenwort³

et al. 2020

Blood Advances

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In an attempt to identify novel markers and immunological targets in leukemic stem cells (LSCs) in acute myeloid leukemia (AML) and chronic myeloid leukemia (CML), we screened bone marrow (BM) samples from patients with AML (n = 274) or CML (n = 97) and controls (n = 288) for expression of cell membrane antigens on CD34+/CD38− and CD34+/CD38+ cells by multicolor flow cytometry. In addition, we established messenger RNA expression profiles in purified sorted CD34+/CD38− and CD34+/CD38+ cells using gene array and quantitative polymerase chain reaction. Aberrantly expressed markers were identified in all cohorts. In CML, CD34+/CD38− LSCs exhibited an almost invariable aberration profile, defined as CD25+/CD26+/CD56+/CD93+/IL-1RAP+. By contrast, in patients with AML, CD34+/CD38− cells variably expressed “aberrant” membrane antigens, including CD25 (48%), CD96 (40%), CD371 (CLL-1; 68%), and IL-1RAP (65%). With the exception of a subgroup of FLT3 internal tandem duplication–mutated patients, AML LSCs did not exhibit CD26. All other surface markers and target antigens detected on AML and/or CML LSCs, including CD33, CD44, CD47, CD52, CD105, CD114, CD117, CD133, CD135, CD184, and roundabout-4, were also found on normal BM stem cells. However, several of these surface targets, including CD25, CD33, and CD123, were expressed at higher levels on CD34+/CD38− LSCs compared with normal BM stem cells. Moreover, antibody-mediated immunological targeting through CD33 or CD52 resulted in LSC depletion in vitro and a substantially reduced LSC engraftment in NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice. Together, we have established surface marker and target expression profiles of AML LSCs and CML LSCs, which should facilitate LSC enrichment, diagnostic LSC phenotyping, and development of LSC-eradicating immunotherapies.

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Section: Discussionmentioning

confidence: 99%

Delineation of target expression profiles in CD34+/CD38− and CD34+/CD38+ stem and progenitor cells in AML and CML

Herrmann

Sadovnik²,

Eisenwort³

et al. 2020

Blood Advances

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“…5 ). Importantly, as IL1RAP is also overexpressed in HSPC of chronic myeloid leukemia ( Järås et al, 2010 ; Gerber et al, 2013 ; Herrmann et al, 2014 ; Zhao et al, 2014 ; Sadovnik et al, 2017 ; Warfvinge et al, 2017 ) and high-risk MDS ( Barreyro et al, 2012 ; Shastri et al, 2017 ), and a recent paper has uncovered that IL1RAP has an active super enhancer in AML ( McKeown et al, 2017 ), there is significant therapeutic potential in further developing IL1RAP-directed targeting strategies.…”

Section: Discussionmentioning

confidence: 99%

“…In acute myeloid leukemia (AML), there is a current need for molecular understanding of pathways relevant in disease initiation and for targeted therapies that selectively and directly inhibit these pathways. We and others previously identified the surface molecule IL-1 receptor accessory protein (IL1RAP) as consistently overexpressed in AML hematopoietic stem and progenitor cells (HSPC) across multiple genetic subtypes of AML ( Barreyro et al, 2012 ; Askmyr et al, 2013 ; Ho et al, 2016 ; Sadovnik et al, 2017 ), as well as in high-risk myelodysplastic syndromes (MDS), hematologic malignancies that often progress to AML. As a result of low IL1RAP expression on normal HSPCs ( Barreyro et al, 2012 ; Ho et al, 2016 ) and apparent dispensability of IL1RAP for the viability of mammalian organisms ( Cullinan et al, 1998 ), IL1RAP has emerged as a promising target for leukemic stem cell (LSC)-directed immunotherapeutic approaches in myeloid malignancies ( Järås et al, 2010 ; Askmyr et al, 2013 ; Herrmann et al, 2014 ; Ågerstam et al, 2015 ; Jiang et al, 2016 ; Landberg et al, 2016 ; Warfvinge et al, 2017 ); however, little is known about whether IL1RAP has a cell-intrinsic role in AML.…”

Section: Introductionmentioning

confidence: 99%

IL1RAP potentiates multiple oncogenic signaling pathways in AML

Mitchell

Barreyro

Todorova

et al. 2018

Journal of Experimental Medicine

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“…Menon et al have also reported that rs4624606 was associated with higher amniotic fluid-1β concentrations (37). IL1RAP may also play a role in acute myeloid leukemia (AML) as well as in high-risk myelodysplastic syndromes, hematologic malignancies that often progress to AML (38)(39)(40)(41).…”

Section: Discussionmentioning

confidence: 99%

The Role of SNPs in IL1RL1 and IL1RAP Genes in Age-related Macular Degeneration Development and Treatment Efficacy

Vilkeviciute

Bastikaityte

Mockutė

et al. 2020

In Vivo

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Background: Age-related macular degeneration (AMD) affects the central part of the retina and causes blindness. In developed countries, AMD occurs in people over 50 years old. Important factors for AMD pathogenesis are an immune response, inflammation, and genetic factors. This study aimed to determine the impact of IL1RL1 rs1041973 and IL1RAP rs4624606 single nucleotide polymorphisms (SNPs) on the occurrence of AMD and the outcome of treatment with aflibercept and bevacizumab. Patients and Methods: 563 patients with AMD and 281 healthy candidates were evaluated. Patients with exudative AMD were treated with intravitreal bevacizumab and aflibercept and, after 6 months based on the changes in bestcorrected visual acuity and central macular thickness, were classified as 'responders' or 'poor-responders'. Genotyping of IL1RL1 rs1041973 and IL1RAP rs4624606 was accomplished using real-time PCR. Age was compared using the Mann-Whitney U-test. Categorical data (gender, genotype, and allele distributions) compared between groups using the χ 2 test or the Fisher's exact test. Associations of gene polymorphisms were calculated using logistic regression analysis with adjustment for age in exudative and atrophic AMD analysis. An adjusted significance threshold for multiple comparisons α=0.025 was applied. Results: Statistically significant differences in the distribution of IL1RAP rs4624606 genotypes (TT, TA and AA) were found between males with atrophic AMD and controls: 50%, 42.9% and 7.1% vs. 69.7%, 30.3% and 0%, respectively, p=0.015. Moreover, we found that 'responders' had a significantly better best-corrected visual acuity than 'poor-responders' before treatment (p=0.032). The central macular thickness was significantly lower in exudative AMD patients with IL1RL1 rs1041973 AA genotype than in wild type and heterozygous (CC+CA) genotype carriers before treatment (p=0.017). Conclusion: IL1RAP rs4624606 may be associated with atrophic AMD in males while IL1RL1 rs1041973 may play a protective role against macular thickening in exudative AMD patients. Age-related macular degeneration (AMD), the leading cause of blindness in developed countries, is a complex disease caused entirely by environmental, demographic, and genetic factors (1, 2). AMD is classified into early or intermediate stages with the formation of drusen, an amorphous extracellular deposit in the retina, and characteristic pigmentary changes, and late stages, which may either be atrophic (geographic atrophy) or wet (neovascular type) (3). Early stages of the disease are often clinically asymptomatic. It progresses slowly and evolves into late AMD only in 10-20% of patients, of which two-thirds have neovascular and one-third atrophic AMD type (4). Late forms are characterized by the irreversible loss of central vision. Treatment in clinical practice is currently available only for the neovascular type: intraocular injections with VEGF inhibitors; there are no clinically approved treatment options for atrophic AMD and/or the possibility to stop early AMD forms...

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Expression of CD25 on leukemic stem cells in BCR-ABL1+ CML: Potential diagnostic value and functional implications

Cited by 34 publications

References 64 publications

Delineation of target expression profiles in CD34+/CD38− and CD34+/CD38+ stem and progenitor cells in AML and CML

Delineation of target expression profiles in CD34+/CD38− and CD34+/CD38+ stem and progenitor cells in AML and CML

IL1RAP potentiates multiple oncogenic signaling pathways in AML

The Role of SNPs in IL1RL1 and IL1RAP Genes in Age-related Macular Degeneration Development and Treatment Efficacy

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