[Frontiers in Bioscience S3, 487-500, January 1, 2011]

The stem cell fitness landscape and pathways of molecular leukemogenesis

Grover C. Bagby1,2,3, Angela G. Fleischman1

1Department of Medicine, Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, Oregon 97239, 2 Knight Cancer Institute at Oregon Health and Science University, Portland, Oregon 97239, 3 NW VA Cancer Research Center, Portland, Oregon, 97239

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Canonical leukemogenesis
4. Altering selection coefficients in stem cell pools
4.1. Selection Coefficients defined
4.2. Enhanced fitness of the new clone relative to cells in a normal stem cell pool
4.3. Altering the coefficient of selection by reducing fitness of stem cells in the untransformed pool
5. The fitness landscape
5.1. Lessons from lava dwellers
5.2. Molecular pathogenesis of aplastic anemia
5.3. Clonal evolution in acquired aplastic anemia
5.4. Molecular pathogenesis of Fanconi anemia
5.5. Overproduction of cytokines by FA cells
5.6. Bad stem cell pools in marrow failure states
6. Clonal evolution in Fanconi anemia
6.1. Adaptive responses
6.2. Myelodysplasia and AML
7. Generalization of the model
7.1. JAK2 mutations and myeloproliferative diseases
8. Implications of clonal adaptation
8.1. Oncogene addiction
8.2. Oncogenes vs. non-oncogenes: distinguishing "passengers" from "drivers"
8.3. Leukemia Prevention
9. Acknowledgements
10. References

1. ABSTRACT

The relative risk of clonal evolution to either myelodysplasia (MDS) or acute myelogenous leukemia (AML) is high in patients with chronic bone marrow failure. From 10 to 20% of acquired aplastic anemia survivors will develop clonal evolution within the decade following their diagnosis as will 40% of patients with some of the inherited bone marrow failure syndromes. Studies on bone marrow failure states have provided some perspective on molecular pathogenesis of marrow failure and have also provided insights on the adaptive nature of clonal evolution. We review the scientific evidence validating this model, emphasize the importance of the fitness landscape in the stem cell pool, outline the clinical and investigative implications of the model, suggest that the lack of fitness in the starting pool accounts for the phenomenon of oncogene addiction, promote the value of the model for the evaluation of prevention strategies, and argue that experiments focusing attention on the relative phenotypes of neoplastic stem cell clones and pools of unfit stem cells from which they evolved will provide a useful paradigm of carcinogenesis in general.