Chronic Myeloid Leukemia CD34+ cells have reduced uptake of imatinib due to low OCT-1 Activity

Engler, JR; Frede, Amity; Saunders, Verity A.; Zannettino, Andrew C.W.; Hughes, Timothy P.; White, Deborah L.

doi:10.1038/leu.2010.16

Cited by 60 publications

(53 citation statements)

References 42 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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“…17,18,95 These rare leukemic cells also share in their possession of multiple unique features that would be expected to promote both common and acquired mechanisms of resistance to BCR-ABL-targeted therapeutics. 19,20,22,[96][97][98][99][100] The latter include the greatly increased expression of BCR-ABL in primitive (CD34 þ CD38 À ) CML cells (a 4100-fold increase in transcripts and a 3-10-fold increase in protein and kinase activity) that appears to be independent of the cycling status of the cells. 19,20,40,62,101 These cells also display a selectively low and high level of expression of various transporters critical for obtaining useful levels of the drug intracellularly.…”

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

confidence: 99%

“…For example, OCT1, the gene that encodes a key transporter required for IM uptake, 102,103 is expressed at extremely low levels in primitive CML cells. 20,98 Similarly, ABCB1 (MDR) and ABCG2, two genes that encode key transporters that efflux many drugs are expressed at selectively elevated levels on primitive CML cells. 20,104,105 Heightened genomic instability has long been thought to be a feature of CML and in the last decade quantitative measurements have now provided definitive evidence that the BCR-ABL fusion gene markedly enhances the genomic instability in hematopoietic 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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“…[8][9][10][11][12] CML persistence supposedly results from an inherent insensitivity to IM of the CML stem and progenitor cells. [13][14][15] Various mechanisms may account for CML persistence under IM, including, for example, BCR-ABL overexpression, 14,16,17 drug in-and efflux mechanisms, [18][19][20] and ABL kinase point mutations. 21 Alternatively, the number of patients with undetectable BCR-ABL transcripts rises with longer IM treatment duration and approached 52% after 5 years in a subcohort of The International Randomized Study of Interferon and STI571.…”

Section: Introductionmentioning

confidence: 99%

Low BCR-ABL expression levels in hematopoietic precursor cells enable persistence of chronic myeloid leukemia under imatinib

Kumari

Brendel

Hochhaus

et al. 2012

Blood

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Chronic Myeloid Leukemia CD34+ cells have reduced uptake of imatinib due to low OCT-1 Activity

Cited by 60 publications

References 42 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

Insights into the stem cells of chronic myeloid leukemia

Low BCR-ABL expression levels in hematopoietic precursor cells enable persistence of chronic myeloid leukemia under imatinib

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