A gene expression signature of CD34+ cells to predict major cytogenetic response in chronic-phase chronic myeloid leukemia patients treated with imatinib

McWeeney, Shannon K.; Pemberton, Lucy C.; Loriaux, Marc; Vartanian, Kristina; Willis, Stephanie G.; Yochum, Gregory S.; Wilmot, Beth; Turpaz, Yaron; Pillai, Raji; Druker, Brian J.; Snead, Jennifer L.; MacPartlin, Mary; O’Brien, Stephen G.; Melo, Junia V.; Lange, Thoralf; Harrington, Christina A.; Deininger, Michael W.

doi:10.1182/blood-2009-03-210732

Cited by 116 publications

(120 citation statements)

References 40 publications

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“…However, there is no compelling evidence that OCTNs are actively involved in imatinib transport, corroborating our own findings in HEK293 cells that carnitine, a high-affinity OCTN substrate, does not interfere with the IUR of imatinib. Furthermore, overexpression of SLC22A4 in COS-7 cells had no effect on the IUR of imatinib (McWeeney et al, 2010). Altogether, these data indicate that none of the known imatinib transporters plays a prominent role in the IUR of imatinib in HEK293 cells.…”

Section: Discussionsupporting

confidence: 52%

Lysosomal Sequestration Determines Intracellular Imatinib Levels

et al. 2015

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The intracellular uptake and retention (IUR) of imatinib is reported to be controlled by the influx transporter SLC22A1 (organic cation transporter 1). We recently hypothesized that alternative uptake and/or retention mechanisms exist that determine intracellular imatinib levels. Here, we systematically investigate the nature of these mechanisms. Imatinib uptake in cells was quantitatively determined by liquid chromatography-tandem mass spectrometry. Fluorescent microscopy was used to establish subcellular localization of imatinib. Immunoblotting, cell cycle analyses, and apoptosis assays were performed to evaluate functional consequences of imatinib sequestration. Uptake experiments revealed high intracellular imatinib concentrations in HEK293, the leukemic cell lines K562 and SD-1, and a gastrointestinal stromal tumor cell line GIST-T1. We demonstrated that imatinib IUR is time-, dose-, temperature-, and energy-dependent and provide evidence that SLC22A1 and other potential imatinib transporters do not substantially contribute to the IUR of imatinib. Prazosin, amantadine, NH 4 Cl, and the vacuolar ATPase inhibitor bafilomycin A1 significantly decreased the IUR of imatinib and likely interfere with lysosomal retention and accumulation of imatinib. Costaining experiments with LysoTracker Red confirmed lysosomal sequestration of imatinib. Inhibition of the lysosomal sequestration had no effect on the inhibition of c-Kit signaling and imatinib-mediated cell cycle arrest but significantly increased apoptosis in imatinib-sensitive GIST-T1 cells. We conclude that intracellular imatinib levels are primarily determined by lysosomal sequestration and do not depend on SLC22A1 expression.

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Section: Discussionsupporting

confidence: 52%

Lysosomal Sequestration Determines Intracellular Imatinib Levels

et al. 2015

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“…45 Recent evidence also points toward an inherent, a priori genetic phenotype of patients that may be predisposed to imatinib resistance and disease progression. 46 Whether alternative treatment can reduce the risk of progressive in this patient population remains an interesting but unanswered question.…”

Section: Spotlightmentioning

confidence: 99%

Seeking the causes and solutions to imatinib-resistance in chronic myeloid leukemia

2010

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Although only 5000 new cases of chronic myeloid leukemia (CML) were seen in the United States in 2009, this neoplasm continues to make scientific headlines year-after-year. Advances in understanding the molecular pathogenesis coupled with exciting developments in both drug design and development, targeting the initiating tyrosine kinase, have kept CML in the scientific limelight for more than a decade. Indeed, imatinib, a small-molecule inhibitor of the leukemia-initiating Bcr-Abl tyrosine kinase, has quickly become the therapeutic standard for newly diagnosed chronic phase-CML (CP-CML) patients. Yet, nearly one-third of patients will still have an inferior response to imatinib, either failing to respond to primary therapy or demonstrating progression after an initial response. Significant efforts geared toward understanding the molecular mechanisms of imatinib resistance have yielded valuable insights into the cellular biology of drug trafficking, enzyme structure and function, and the rational design of novel small molecule enzyme inhibitors. Indeed, new classes of kinase inhibitors have recently been investigated in imatinibresistant CML. Understanding the pathogenesis of tyrosine kinase inhibitor resistance and the molecular rationale for the development of second and now third generation therapies for patients with CML will be keys to further disease control over the next 10 years.

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“…The close interdependence between the bone marrow vessels and the hematopoietic cells has long been appreciated. Recent interest in bone marrow vascularity has brought to light the production of hematopoietic growth factors by endothelial cells [8,9]. These capillaries and sinusoids are functionally dormant and non-patent in a normal marrow which accounts for sparse MVD in a normal marrow.…”

Section: Discussionmentioning

confidence: 99%

Does CD34 Staining Reflect the Angiogenic Process in the Bone Marrow? An Analysis of a Series of Chronic Myeloid Leukemia Patients

Mahadevan

Basu

Kumar

2014

JCDR

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Backgorund: Angiogenesis is associated with growth, dissemin ation and metastasis of tumours. Measurement of Microvascular Density (MVD) is a quantitative method of assessment of angio genesis and would give a proportional co relate of the angiogenic process in tumours. The aim of this study is to measure the MVD by using CD34 staining in various phases of Chronic Myeloid Leukemia (CML) and type of CML (Granulocytic/Granulocytic Megakaryocytic) (G/GM) and to co relate micro vascular densities with the grade of fibrosis. Materials and Methods:Bone marrow biopsy specimens of 30 CML patients and 20 non CML (controls) cases that required bone marrow biopsy were subjected to CD34 staining and H&E staining. The mean MVD in CD34 slides was assessed by selecting hot spots and MVD was measured in these fields in high power (40 x magnification) and the mean MVD was calculated by taking the average of four hot spots per field. Grade of fibrosis and phase of CML, type (G/GM) were assessed in H&E slides. The controls were matched with respect to age and gender.Results: Among 30 patients with CML, 21 were in chronic phase, five in accelerated and four in blast crisis. A normal distribution was obtained for MVD of both CML cases and controls using tests for normality. Comparison of mean MVD between CML and controls by student t test showed a significant increase in MVD of CML cases (p = 0.00026). However, no significant difference in MVD between the three phases viz, Chronic, accelerated and blast crisis phase (p = 0.302) was obtained by using one way ANOVA. Comparison of Grade of fibrosis with MVD using independent t test showed no significant difference in MVD between low (Grade1&2) and high grade (Grade 3&4) (p = 0.805). No significant difference in MVD was obtained between G and GM types of CML using independent t test (p =0.381). Conclusion:The study shows that there is a significant increase in MVD in CML cases than controls but no significant difference in MVD could be demonstrated between different phases of CML, histological types of CML and grades of fibrosis in CML.

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A gene expression signature of CD34+ cells to predict major cytogenetic response in chronic-phase chronic myeloid leukemia patients treated with imatinib

Cited by 116 publications

References 40 publications

Lysosomal Sequestration Determines Intracellular Imatinib Levels

Lysosomal Sequestration Determines Intracellular Imatinib Levels

Seeking the causes and solutions to imatinib-resistance in chronic myeloid leukemia

Does CD34 Staining Reflect the Angiogenic Process in the Bone Marrow? An Analysis of a Series of Chronic Myeloid Leukemia Patients

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