February 2010 Paper of the month

This month's featured paper is from the Journal of Clinical Investigation, and is titled "Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity." 

This research was conducted as part of an investigative collaboration led by Brian J. Druker, MD, Director, OHSU Knight Cancer Institute, and Investigator, Howard Hughes Medical Institute (HHMI); Michael W. Deininger, MD, PhD; Amie S. Corbin, Research Technician III, HHMI; Anupriya Agarwal, PhD, Postdoctoral Researcher; and colleagues.*

Chronic myeloid leukemia (CML) is a disease of the hematopoietic stem cell characterized by excessive proliferation of white blood cells in the bone marrow. It is caused by BCR-ABL, a constitutively active tyrosine kinase that results from a specific rearrangement of chromosomes 9 and 22. Targeted therapy with the ABL kinase inhibitor imatinib (Gleevec) has transformed CML from a life-threatening disease into a chronic condition, with nearly 90 percent of patients attaining durable remission by five years on therapy. Despite these impressive responses, BCR-ABL often remains detectable by polymerase chain reaction (PCR)-based assays, and disease recurrence usually occurs upon discontinuation of the drug, even in patients who are negative by PCR. This indicates that leukemogenic cells survive even in the best responders – a state referred to as disease persistence. Therefore, lifelong therapy is currently recommended, which incurs a substantial financial cost to patients and can be associated with significant side effects.

The observation that a patient's disease may persist at low levels for a prolonged period of time on imatinib therapy argues that the imatinib-resistant cell populations must contain leukemia stem cells with self-renewal capacity. The critical question from a therapeutic standpoint is whether CML stem cell survival – and hence disease persistence – is dependent upon or independent of BCR-ABL kinase activity. Elucidating the answer to this central question is crucial to directing strategies to eradicate residual leukemia.

In this study, the authors critically investigated whether BCR-ABL is indeed a therapeutic target in primary CML stem cells associated with disease persistence. They showed that BCR-ABL was constitutively activated in both stem cells and more mature progenitor cells (which lack self-renewal capacity) from newly diagnosed CML patients and found that imatinib potently inhibited BCR-ABL kinase activity to equal extents in cells from each compartment. "These findings strongly suggest that human CML stem cells do not depend on BCR-ABL activity for survival and are thus not eliminated by imatinib therapy or by more potent second generation ABL kinase inhibitors," said Amie Corbin.

As earlier studies have proposed stem cell quiescence – a "hibernation-like" state of arrested cell cycling and division – as a potential mechanism by which primitive CML cells may escape the cytotoxic effects of imatinib, the authors also examined whether BCR-ABL activity mediates the survival of these quiescent cells. Their results clearly demonstrated that quiescent CML stem cells survive in the presence of imatinib. Furthermore, as such quiescent cells reside in the protective, cytokine-rich microenvironment of the bone marrow, the authors also showed that while short-term imatinib treatment reduced the expansion of CML stem and progenitor cells, cytokine support permitted growth and survival in the absence of BCR-ABL activity that was comparable to that of normal stem and progenitor cells.

Taken together, these findings demonstrate that primitive CML cells are capable of BCR-ABL-independent survival and suggest therapies that biochemically target BCR-ABL will not eliminate CML stem cells. This has important implications for developing curative therapeutic approaches in CML, with future studies now focusing on delineating the alternative mechanisms responsible for CML stem cell survival. "Improved understanding of such mechanisms will not only guide design of rationale strategies to eradicate residual CML cells as a means to achieve a cure, but may also prove applicable to addressing similar issues in other cancers," said Dr. Agarwal.

Read paper at the Journal of Clinical Investigation.

From the OHSU Knight Cancer Institute, Division of Hematology and Medical Oncology: Brian J. Druker, Michael W. Deininger, Amie S. Corbin, Anupriya Agarwal, and Marc Loriaux; also from the Department of Pathology: Marc Loriaux; From the M. D. Anderson Cancer Center: Jorge Cortes. Amie S. Corbin and Anupriya Agarwal as well as Brian J. Druker and Michael W. Deininger, contributed equally to this work.


Figure 8 Model of CML disease persistence with imatinib treatment. Orange cells represent CML cells in a BCR-ABL-active state. Grey cells indicate lack of BCR-ABL activity. These cells are either normal (non-leukemic), or CML cells in which BCR-ABL is supressed by imatinib treatment. Brown cells represent stroma and small dark brown circles are secreted cytokines.

(A) BCR-ABL activity drives expansion of primitive CML cells. (B) Imatinib treatment inhibits BCR-ABL activity in CML stem cells, restoring normal homeostasis and eliminating the proliferative advantage of leukemic cells. Normal hematopoiesis is re-established; however, the bone marrow microenvironment supports survival of CML stem cells that are not oncogene addicted.


Pictured : (top) JCI cover; (middle) Amie Corbin first author, Anupriya Agarwal, second author, who share equal contribution to paper; (bottom) Figure 8 model

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ABOUT THE PAPER OF THE MONTH

The School of Medicine newsletter spotlights a recently published faculty research paper in each issue. The goals are to highlight the great research happening at OHSU and to share this information across departments, institutes and disciplines. The monthly paper summary is selected by Associate Dean for Basic Science Mary Stenzel-Poore, PhD, and reviewed by Dean Mark Richardson, MD, MBA, and Vice President/Senior Associate Dean for Research Dan Dorsa, PhD.

This paper was selected because it reveals a critically important feature of BCR-ABL and its relationship to the persistence of CML cells—namely that inhibition of the growth of these cancer cells by treatment with the imatinib causes disease remission, but does not lead to permanent cure because CML stem cells can survive in the absence of BCR-ABL activity. This finding emphasizes the importance of ongoing studies to find new strategies that eliminate CML cells permanently.