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Acute Non Lymphocytic Leukemia

Quantitative single cell determination of ERK phosphorylation and regulation in relapsed and refractory primary acute myeloid leukemia

Leukemia volume 19, pages 1543–1549 (2005)Cite this article

Abstract

We investigated the constitutive activation of the MEK/ERK pathway in acute myelogenous leukemia (AML) via a flow cytometric technique to quantitate expression of phosphorylated ERK (p-ERK). A total of 42 AML samples (16 newly diagnosed, 26 relapsed/refractory) were analyzed. Normal bone marrow CD34+ cells (n=10) had little or no expression of p-ERK, while G-CSF-mobilized CD34+ cells exhibited enhanced p-ERK levels. Markedly elevated p-ERK levels were found in 83.3% of the AML samples, with no differences observed between the newly diagnosed and relapsed/refractory samples. Treatment with a MEK inhibitor resulted in significantly decreased p-ERK levels in both the newly diagnosed and relapsed/refractory samples, which was associated with growth arrest, but not apoptosis induction. In summary, we defined conditions for the analysis of MAPK signaling in primary AML samples. Normal CD34+ cells expressed very low levels of p-ERK, and increased p-ERK levels were found in normal G-CSF-stimulated circulating CD34+ cells. Constitutively high p-ERK levels observed in the majority of AML samples suggest deregulation of this pathway that appears to be independent of disease status. The ability of ERK inhibition to promote growth arrest rather than apoptosis suggests that clinical trials of MEK/ERK inhibitors may be more effective when combined with chemotherapy.

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Acknowledgements

This work was supported in part by grants from the National Cancer Institute (PO1 CA55164 and CA16672) (to MA).

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Authors and Affiliations

  1. Departments of Blood and Marrow Transplantation, Section of Molecular Hematology and Therapy, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA

    M R Ricciardi, T McQueen, D Chism, M Milella, M Konopleva & M Andreeff

  2. Department of Leukemia, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA

    E Estey & M Andreeff

  3. Cancer Molecular Sciences Department, Pfizer Global Research & Development, Ann Arbor, MI, USA

    E Kaldjian & J Sebolt-Leopold

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  1. M R Ricciardi
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  2. T McQueen
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Correspondence to M Andreeff.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu).

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Ricciardi, M., McQueen, T., Chism, D. et al. Quantitative single cell determination of ERK phosphorylation and regulation in relapsed and refractory primary acute myeloid leukemia. Leukemia 19, 1543–1549 (2005). https://doi.org/10.1038/sj.leu.2403859

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