IL1RAP expression as a measure of leukemic stem cell burden at diagnosis of chronic myeloid leukemia predicts therapy outcome

Landberg, Niklas; Hansen, Nils; Askmyr, Maria; Ågerstam, Helena; Lassen, Carin; Rissler, Marianne; Hjorth‐Hansen, Henrik; Mustjoki, Satu; Järås, Marcus; Richter, Johan; Fioretos, Thoas

doi:10.1038/leu.2015.135

Cited by 43 publications

(40 citation statements)

References 15 publications

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“…In accordance with previous observations, IL1RAP marked the vast majority of CML LSCs, while not all BCR-ABL pos cells expressed CD26 and CD25. 32 Of note, only subpopulations with a late myeloid or lymphoid molecular signature were CD45RA 1 supporting previous reports describing that quiescent, diagnostic CML LSCs reside in the Lin…”

Section: Cd38supporting

confidence: 52%

Single-cell molecular analysis defines therapy response and immunophenotype of stem cell subpopulations in CML

Warfvinge¹,

Geironson²,

Sommarin³

et al. 2017

Blood

116

120

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Section: Cd38supporting

confidence: 52%

Single-cell molecular analysis defines therapy response and immunophenotype of stem cell subpopulations in CML

Warfvinge¹,

Geironson²,

Sommarin³

et al. 2017

Blood

116

120

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“…More recently, a series of genes were identified by transcriptome analysis [14]. Both IL1RAP and CD26 can be regarded as promising candidates as CML-specific antigens in the CD34 + CD38 − CML LSC population [15–17]. Within this context, PTPRG has unique features as it is specifically downregulated in CML and has been demonstrated to have a functional role being capable of binding and dephosphorylating the driving oncoprotein BCR-ABL1 and consequently reducing total and specific phosphotyrosine levels as well as clonogenic capacity in various CML cells [8].…”

Section: Discussionmentioning

confidence: 99%

“…Few protein biomarkers have been described and implemented for CML diagnosis or management, most are overexpressed, often not CML specific and, overall, need to be better characterized and validated in the clinic [11–14]. An exception to this general picture might be CD26 and IL1RAP that were very recently described as a CD34 + /CD38 − CML leukemia stem cell (LSC)-associated biomarker [15–17]. Overall cell surface antigens deserve more in-depth characterization as they have the potential to represent a complementary, robust, and straightforward method for monitoring the disease and may represent potential therapeutic targets [11–13].…”

Section: Introductionmentioning

confidence: 99%

A new monoclonal antibody detects downregulation of protein tyrosine phosphatase receptor type γ in chronic myeloid leukemia patients

et al. 2017

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BackgroundProtein tyrosine phosphatase receptor gamma (PTPRG) is a ubiquitously expressed member of the protein tyrosine phosphatase family known to act as a tumor suppressor gene in many different neoplasms with mechanisms of inactivation including mutations and methylation of CpG islands in the promoter region. Although a critical role in human hematopoiesis and an oncosuppressor role in chronic myeloid leukemia (CML) have been reported, only one polyclonal antibody (named chPTPRG) has been described as capable of recognizing the native antigen of this phosphatase by flow cytometry. Protein biomarkers of CML have not yet found applications in the clinic, and in this study, we have analyzed a group of newly diagnosed CML patients before and after treatment. The aim of this work was to characterize and exploit a newly developed murine monoclonal antibody specific for the PTPRG extracellular domain (named TPγ B9-2) to better define PTPRG protein downregulation in CML patients.MethodsTPγ B9-2 specifically recognizes PTPRG (both human and murine) by flow cytometry, western blotting, immunoprecipitation, and immunohistochemistry.ResultsCo-localization experiments performed with both anti-PTPRG antibodies identified the presence of isoforms and confirmed protein downregulation at diagnosis in the Philadelphia-positive myeloid lineage (including CD34+/CD38bright/dim cells). After effective tyrosine kinase inhibitor (TKI) treatment, its expression recovered in tandem with the return of Philadelphia-negative hematopoiesis. Of note, PTPRG mRNA levels remain unchanged in tyrosine kinase inhibitors (TKI) non-responder patients, confirming that downregulation selectively occurs in primary CML cells.ConclusionsThe availability of this unique antibody permits its evaluation for clinical application including the support for diagnosis and follow-up of these disorders. Evaluation of PTPRG as a potential therapeutic target is also facilitated by the availability of a specific reagent capable to specifically detect its target in various experimental conditions.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-017-0494-z) contains supplementary material, which is available to authorized users.

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“…However, the identification of LSCs and their separation from normal hematopoietic stem cells (HSCs) in CML is challenging, since both populations reside in the same compartment phenotypically defined as CD45 + 34 + 38 − [10]. Recently, several groups have reported on more or less specific LSC markers and LSC-related light scatter properties in CML [10–16]. One of such markers appears to be IL-1RAP, while another is CD26, which is also known as dipeptidylpeptidase IV (DPPIV).…”

Section: Introductionmentioning

confidence: 99%

Quantitative assessment of the CD26+ leukemic stem cell compartment in chronic myeloid leukemia: patient-subgroups, prognostic impact, and technical aspects

et al. 2016

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Little is known about the function and phenotype of leukemic stem cells (LSCs) in chronic myeloid leukemia (CML) or about specific markers that discriminate LSCs from normal hematopoietic stem cells (HSCs). CD26 has recently been described as a specific marker of CML LSCs. In the current study, we investigated this marker in a cohort of 31 unselected CML patients. BCR/ABL1 positivity was analyzed in highly enriched stem cell fractions using fluorescence in situ hybridization (FISH) and reverse transcription PCR (RT-PCR). The proportion of CD26+ LSCs and CD26− HSCs varied considerably among the patients analyzed, and the percentage of CD26+ cells correlated with leukocyte count. The CD26 expression robustly discriminated LSCs from HSCs. This required a strict gating of the stem cell compartment. Thus, in patients with very low LSC or HSC numbers, only the highly sensitive RT-PCR method discriminated between clonal and non-clonal cells, while a robust FISH analysis required larger numbers of cells in both compartments. Finally, our data show that the numbers of CD26+ CML LSCs correlate with responses to treatment with BCR-ABL1 inhibitors.

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IL1RAP expression as a measure of leukemic stem cell burden at diagnosis of chronic myeloid leukemia predicts therapy outcome

Cited by 43 publications

References 15 publications

Single-cell molecular analysis defines therapy response and immunophenotype of stem cell subpopulations in CML

Single-cell molecular analysis defines therapy response and immunophenotype of stem cell subpopulations in CML

A new monoclonal antibody detects downregulation of protein tyrosine phosphatase receptor type γ in chronic myeloid leukemia patients

Quantitative assessment of the CD26+ leukemic stem cell compartment in chronic myeloid leukemia: patient-subgroups, prognostic impact, and technical aspects

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