Properties of CD34+ CML stem/progenitor cells that correlate with different clinical responses to imatinib mesylate

Jiang, Xiaoyan; Forrest, Donna L.; Nicolini, Franck E.; Turhan, Ali G.; Guilhot, Joëlle; Yip, Calvin K.; Holyoake, Tessa L.; Jørgensen, Heather G.; Lambie, Karen; Saw, Kyi Min; Pang, Emily; Vukovic, Ranko; Lehn, P; Ringrose, Ashley; Yu, Miao; Brinkman, Ryan R.; Smith, Clay; Eaves, Allen C.; Eaves, Connie J.

doi:10.1182/blood-2009-05-222471

Cited by 56 publications

(58 citation statements)

References 46 publications

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“…The reason that CML stem cells are partially resistant to TKIs, such as imatinib (Gleevec, Novartis Inc.) is unclear, but factors that have been suggested to contribute to this resistance include quiescence, relatively high levels of BCR/ABL1 expression, ac- quired mutations in BCR/ABL1, and combinatorial expression of specific membrane transporter proteins in these cells (7,8,(27)(28)(29). Given these features, novel treatment approaches to ultimately eradicate the CML stem cells are highly desirable.…”

Section: Discussionmentioning

confidence: 99%

Isolation and killing of candidate chronic myeloid leukemia stem cells by antibody targeting of IL-1 receptor accessory protein

Järås

Johnels

Hansen

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

161

114

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Chronic myeloid leukemia (CML) is genetically characterized by the Philadelphia (Ph) chromosome, formed through a reciprocal translocation between chromosomes 9 and 22 and giving rise to the constitutively active tyrosine kinase P210 BCR/ABL1. Therapeutic strategies aiming for a cure of CML will require full eradication of Ph chromosome-positive (Ph + ) CML stem cells. Here we used geneexpression profiling to identify IL-1 receptor accessory protein (IL1RAP) as up-regulated in CML CD34 + cells and also in cord blood CD34 + cells as a consequence of retroviral BCR/ABL1 expression. To test whether IL1RAP expression distinguishes normal (Ph − ) and leukemic (Ph + ) cells within the CML CD34 + CD38 − cell compartment, we established a unique protocol for conducting FISH on small numbers of sorted cells. By using this method, we sorted cells directly into drops on slides to investigate their Ph-chromosome status. Interestingly, we found that the CML CD34 + CD38 − IL1RAP + cells were Ph + , whereas CML CD34 + CD38 − IL1RAP − cells were almost exclusively Ph − . By performing long-term culture-initiating cell assays on the two cell populations, we found that Ph + and Ph − candidate CML stem cells could be prospectively separated. In addition, by generating an anti-IL1RAP antibody, we provide proof of concept that IL1RAP can be used as a target on CML CD34 + CD38 − cells to induce antibody-dependent cell-mediated cytotoxicity. This study thus identifies IL1RAP as a unique cell surface biomarker distinguishing Ph + from Ph − candidate CML stem cells and opens up a previously unexplored avenue for therapy of CML.antibody-dependent cell-mediated cytotoxicity | cancer | biomarker | therapeutic antibody

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Section: Discussionmentioning

confidence: 99%

Isolation and killing of candidate chronic myeloid leukemia stem cells by antibody targeting of IL-1 receptor accessory protein

Järås

Johnels

Hansen

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

161

114

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“…However, although long-term disease control can be achieved in many patients, imatinib is usually unable to eliminate CML. This phenomenon is best explained by intrinsic and acquired drug resistance in leukemic stem cells, LSC (6)(7)(8)(9)(10)(11)(12). The intrinsic form of resistance is common to all LSC fractions and is considered to be independent of BCR/ABL1.…”

Section: Introductionmentioning

confidence: 99%

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

Sadovnik

Hoelbl-Kovacic

Herrmann

et al. 2016

Clinical Cancer Research

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Purpose: In chronic myelogenous leukemia (CML), leukemic stem cells (LSC) represent a critical target of therapy. However, little is known about markers and targets expressed by LSCs. The aim of this project was to identify novel relevant markers of CML LSCs.Experimental Design: CML LSCs were examined by flow cytometry, qPCR, and various bioassays. In addition, we examined the multipotent CD25 þ CML cell line KU812.

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“…Regardless of the underlying mechanisms, it is important to note that many of these parameters, in particular, the biological (survival) response of CD34 þ CFCs to IM in vitro, OCT1 expression, IM uptake and the frequency of BCR-ABL kinase domain mutations in the CD34 þ population may be useful predicators of clinical IM responses. 103,[112][113][114] Searching for new strategies to eradicate CML stem cells…”

Section: Properties That Affect Responses To Bcr-abl-targeted Therapementioning

confidence: 99%

Insights into the stem cells of chronic myeloid leukemia

et al. 2010

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Chronic myeloid leukemia (CML) has long served as a paradigm for generating new insights into the cellular origin, pathogenesis and improved approaches to treating many types of human cancer. Early studies of the cellular phenotypes and genotypes represented in leukemic populations obtained from CML patients established the concept of an evolving clonal disorder originating in and initially sustained by a rare, multipotent, self-maintaining hematopoietic stem cell (HSC). More recent investigations continue to support this model, while also revealing new insights into the cellular and molecular mechanisms that explain how knowledge of CML stem cells and their early differentiating progeny can predict the differing and variable features of chronic phase and blast crisis. In particular, these emphasize the need for new agents that effectively and specifically target CML stem cells to produce non-toxic, but curative therapies that do not require lifelong treatments.

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Properties of CD34+ CML stem/progenitor cells that correlate with different clinical responses to imatinib mesylate

Cited by 56 publications

References 46 publications

Isolation and killing of candidate chronic myeloid leukemia stem cells by antibody targeting of IL-1 receptor accessory protein

Isolation and killing of candidate chronic myeloid leukemia stem cells by antibody targeting of IL-1 receptor accessory protein

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

Insights into the stem cells of chronic myeloid leukemia

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