Clonal evolution in hematological malignancies and therapeutic implications

Leukemia (2014) 28, 34–43 & 2014 Macmillan Publishers Limited All rights reserved 0887-6924/14 www.nature.com/leu REVIEW Clonal evolution in hematological malignancies and therapeutic implications DA Landau1,2,3,4, SL Carter2, G Getz2,5 and CJ Wu1,6,7 The ability of cancer to evolve and adapt is a principal challenge to therapy in general and to the paradigm of targeted therapy in particular. This ability is fueled by the co-existence of multiple, genetically heterogeneous subpopulations within the cancer cell population. Increasing evidence has supported the idea that these subpopulations are selected in a Darwinian fashion, by which the genetic landscape of the tumor is continuously reshaped. Massively parallel sequencing has enabled a recent surge in our ability to study this process, adding to previous efforts using cytogenetic methods and targeted sequencing. Altogether, these studies reveal the complex evolutionary trajectories occurring across individual hematological malignancies. They also suggest that while clonal evolution may contribute to resistance to therapy, treatment may also hasten the evolutionary process. New insights into this process challenge us to understand the impact of treatment on clonal evolution and inspire the development of novel prognostic and therapeutic strategies. Leukemia (2014) 28, 34–43; doi:10.1038/leu.2013.248 Keywords: cancer evolution; clonal heterogeneity; massively parallel sequencing INTRODUCTION The past decade has been a remarkable period of progress in the treatment of cancer in general and hematological malignancies in particular. Much of this progress has been based on exploiting knowledge of the genetic vulnerabilities of particular cancers so that they can be effectively targeted. For example, the impressive efficacy of tyrosine kinase inhibition (abrogating constitutive Abl kinase activity) for chronic myelogenous leukemia (CML) has unequivocally established the paradigm of targeted therapy for the treatment of malignant disease.1 Likewise, understanding the role of APML-RARA in acute promyelocytic leukemia has led to a highly effective regimen with minimal toxicity that overcomes the effects of this gene fusion and that does not include conventional chemotherapy.2 Collectively, these examples suggest that the promise of precision medicine is finally coming to fruition in the treatment of blood malignancies. At the same time, this revolution has also taught us important humbling lessons. Targeted cancer therapy, even when achieving highly effective responses, typically provides only short-lived relief. The malignant process often finds alternate routes to circumvent the roadblocks imposed on it by targeted monotherapy.3–5 An instructive example is the case of Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia (Ph þ B-ALL). The BCR-ABL1 oncogene is critical for the generation of Ph þ B-ALL, as shown by the high frequency of this lesion in ALL, its adverse prognostic impact,6 and the strong in vitro transformative capacity of this driver.7 The success of imatinib in the treatment of CML encouraged clinicians to attempt to inhibit the BCR-ABL1 oncogene in Ph þ B-ALL. Although a high response rate was observed (70% of patients),8 including in patients with refractory or relapsed disease,9 the responses were uniformly short-lived with disease progression occurring within weeks. High failure rates were also seen with more potent, second-generation, tyrosine kinase inhibitors such as dasatinib,10 with the emergence of drug-resistant clones. Thus, even while the genomic revolution is rapidly expanding the list of potentially targetable genetic lesions,11 the ability of cancer to adapt poses significant limitations to the therapeutic potential of both standard chemotherapy as well as targeted therapies. As reviewed herein, several lines of evidence lead to an increasing appreciation of the plasticity of cancer—its ability to adapt both to host defenses and to therapy—as an additional facet to consider in the selection and timing of cancer therapeutics. CLONAL HETEROGENEITY, THE ENGINE OF CANCER PLASTICITY Genetic plasticity is defined as one of the enabling characteristics of cancer, in which the acquisition of the multiple cancer hallmarks depends on a succession of alterations in the genomes of neoplastic cells.12 This plasticity results from ongoing accumulation of additional somatic mutations that are then positively selected. Cases of convergent evolution have been observed in which the same genetic target may sustain several different somatic mutations within the same tumor, yet affecting different subclones (for example, the case of deletion BTG1 in ALL13). These findings strongly suggest that the lesions we detect at the level of large populations of cancer cells are the products of an astonishing amount of genetic ‘trial and error’ that occurs in every cancerous process at the single-cell level. This high degree of genetic variability provides a ready substrate for an 1 Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, MA, USA; 2Broad Institute, Cambridge, MA, USA; 3Department of Hematology, Yale Cancer Center, New Haven, CT, USA; 4Université Paris Diderot, Paris, France; 5Massachusetts General Hospital Cancer Center and Department of Pathology, Boston, MA, USA; 6Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA and 7Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA. Correspondence: Dr CJ Wu, Dana-Farber Cancer Institute, Harvard Institutes of Medicine, Room 420, 77, Avenue Louis Pasteur, Boston, MA 02115, USA. E-mail: Received 31 May 2013; revised 22 July 2013; accepted 14 August 2013; accepted article preview online 27 August 2013; advance online publication, 1 October 2013 Clonal evolution and therapeutic strategies DA Landau et al 35 evolutionary optimization process, as subclones compete over resources and adapt to external pressures, such as cancer therapy. Cancer progression, therefore, is fundamentally a process of mutational diversification and clonal selection.14 The first experimental evidence supporting the idea that tumors are composed of heterogeneous subpopulations was obtained from mouse models of solid malignancies. These experiments showed that individual subclones possessed different phenotypic characteristics, including varying metastatic potential.15 Importantly, the link between heterogeneity and resistance to therapy was apparent even in other early experiments. For example, cell lines that exhibited a higher degree of phenotypic heterogeneity also acquired resistance to chemotherapy (methotrexate) at a higher rate compared with cell lines with lower phenotypic variability.16 As cancer is a disease that results from the accumulation of genetic alterations,17 a natural corollary of the above studies is that phenotypic evolution must stem from underlying genotypic evolution. This concept has (...truncated)