Identification of CD25 as STAT5-Dependent Growth Regulator of Leukemic Stem Cells in Ph+ CML

Sadovnik, Irina; Hoelbl-Kovacic, Andrea; Herrmann, Harald; Eisenwort, Gregor; Cerny-Reiterer, Sabine; Warsch, Wolfgang; Hoermann, Gregor; Greiner, Georg; Blatt, Katharina; Peter, Barbara; Stefanzl, Gabriele; Berger, Daniela; Bilban, Martin; Herndlhofer, Susanne; Sill, Heinz; Sperr, Wolfgang R.; Streubel, Berthold; Mannhalter, Christine; Holyoake, Tessa L.; Sexl, Veronika; Valent, Peter

doi:10.1158/1078-0432.ccr-15-0767

Cited by 60 publications

(82 citation statements)

References 51 publications

(87 reference statements)

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“…Many groups have attempted to identify novel cell surface markers of the CML LSC. Included in these are CD25, IL1-RAP, and CD26, identified within a CD34 + CD38 −/low CML stem/progenitor cell population [9,32,33]. IL1-RAP and CD26 are arguably the most well established, and have been shown to separate BCR-ABL positive and negative cell populations, as well as being investigated for their potential for targeting therapeutically [10,11,34].…”

Section: Discussionmentioning

confidence: 99%

CD93 is expressed on chronic myeloid leukemia stem cells and identifies a quiescent population which persists after tyrosine kinase inhibitor therapy

et al. 2020

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The introduction of BCR-ABL tyrosine kinase inhibitors has revolutionized the treatment of chronic myeloid leukemia (CML). A major clinical aim remains the identification and elimination of low-level disease persistence, termed "minimal residual disease". The phenomenon of disease persistence suggests that despite targeted therapeutic approaches, BCR-ABLindependent mechanisms exist which sustain the survival of leukemic stem cells (LSCs). Although other markers of a primitive CML LSC population have been identified in the preclinical setting, only CD26 appears to offer clinical utility. Here we demonstrate consistent and selective expression of CD93 on a lin − CD34 + CD38 − CD90 + CML LSC population and show in vitro and in vivo data to suggest increased stem cell characteristics, as well as robust engraftment in patient-derived xenograft models in comparison with a CD93 − CML stem/progenitor cell population, which fails to engraft. Through bulk and single-cell analyses of selected stem cell and cell survival-specific genes, we confirmed the quiescent character and demonstrate their persistence in a population of CML patient samples who demonstrate molecular relapse on TKI withdrawal. Taken together, our results identify that CD93 is consistently and selectively expressed on a lin − CD34 + CD38 − CD90 + CML LSC population with stem cell characteristics and may be an important indicator in determining poor TKI responders.

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Section: Discussionmentioning

confidence: 99%

CD93 is expressed on chronic myeloid leukemia stem cells and identifies a quiescent population which persists after tyrosine kinase inhibitor therapy

et al. 2020

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“…Other examples include expression of cell surface molecules that are linked to signaling pathways in LSCs. In particular, CD25, a STAT5‐dependent cell surface marker, regulates the growth of CML LSCs, which is associated with the PI3K/mTOR pathway . It is hopeful that CD25 could be a legitimate target for eradicating CML LSCs.…”

Section: Strategies For Targeting Lscsmentioning

confidence: 99%

Concise Review: Exploiting Unique Biological Features of Leukemia Stem Cells for Therapeutic Benefit

Zhang

2019

Stem Cells Translational Medicine

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Cancer stem cells play a critical role in disease initiation and insensitivity to chemotherapy in numerous hematologic malignancies and some solid tumors, and these stem cells need to be eradicated to achieve a cure. Key to successful targeting of cancer stem cells is to identify and functionally test critical target genes and to fully understand their associated molecular network in these stem cells. Human chronic myeloid leukemia (CML) is well accepted as one of the typical types of hematopoietic malignancies that are derived from leukemia stem cells (LSCs), serving as an excellent model disease for understanding the biology of LSCs and developing effective, selective, and curative strategies through targeting LSCs. Here, we discuss LSCs in CML with a focus on identification of unique biological features of these stem cells to emphasize the feasibility and significance of specific targeting of LSCs while sparing normal stem cell counterparts in leukemia therapy. Stem Cells Translational Medicine 2019;8:768&774

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“…Additional markers and targets were equally detected on these cells such as CD33 or CD52. Both of these surface antigens are overexpressed in LSC compared with normal hematopoietic stem cells; therefore, targeting these markers with Mylotarg (anti‐CD33 antibody) and Alemtuzumab (anti‐CD52 antibody) may bean interesting therapeutic appraoch …”

Section: Characterizing and Modeling Lscsmentioning

confidence: 99%

What are the challenges in 2016 regarding resistance to tyrosine kinase inhibitors in chronic myeloid leukemia and cancer?

Lewis

Copland

Soverini

et al. 2016

Hematological Oncology

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In the past decade, the treatment of chronic myeloid leukemia (CML) has undergone a drastic evolution. The discovery and success of imatinib and second-generation tyrosine kinase inhibitors have substantially increased the outcome for CML patients. The next step in medical and scientific research is to better understand the malignancy so as to eventually find a cure to eliminate all leukemic cells from patients. One of the key issues is about the resistance of the leukemic stem cells to tyrosine kinase inhibitors. Here, we briefly describe our current studies on CML resistance, and leukemic stem cell modeling and characterization.

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Identification of CD25 as STAT5-Dependent Growth Regulator of Leukemic Stem Cells in Ph+ CML

Cited by 60 publications

References 51 publications

CD93 is expressed on chronic myeloid leukemia stem cells and identifies a quiescent population which persists after tyrosine kinase inhibitor therapy

CD93 is expressed on chronic myeloid leukemia stem cells and identifies a quiescent population which persists after tyrosine kinase inhibitor therapy

Concise Review: Exploiting Unique Biological Features of Leukemia Stem Cells for Therapeutic Benefit

What are the challenges in 2016 regarding resistance to tyrosine kinase inhibitors in chronic myeloid leukemia and cancer?

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