Chronic Myeloid Leukemia: Two Decades that Changed a Disease

Abstract

Michael Deininger speaks to Hannah Branch, Assistant Commissioning Editor: I have a long-standing interest in the biology and therapy of chronic myeloid leukemia (CML). I have trained as a clinician in Nuremberg (Germany), clinical investigator in hematologic malignancies in Leipzig (Germany), Portland (OR, USA) and Salt Lake City (UT, USA), and as a bench scientist in molecular and cellular biology at Imperial College (London, UK). For the past 17 years, starting with my PhD work on imatinib at Imperial College London, I have studied the effects of tyrosine kinase inhibitors (TKIs) on CML, both in the laboratory and as an investigator on numerous clinical trials. My laboratory at Oregon Health & Science University (OR, USA) and at The University Of Utah Huntsman Cancer Institute (UT, USA) has contributed to the understanding of TKI resistance in CML, including the role of mutations in the kinase domain of BCR–ABL1. We have developed assays to predict resistance mutations and established biomarkers to predict response to TKIs. Our studies have contributed to the development of second- and third-generation TKIs, such as ponatinib, and have influenced thinking about CML. Moreover, we have discovered that CML stem cells are independent of BCR–ABL kinase activity, thereby explaining why most CML patients harbor residual leukemia, even after many years of TKI therapy. My laboratory remains committed to addressing clinically important questions in CML. In collaboration with the laboratory of Thomas O’Hare at The Huntsman Cancer Institute (UT, USA) we have now identified compound mutations of BCR–ABL1 as an important mechanism of TKI resistance and are in the process of characterizing these mutations. Furthermore, we have developed the concept that the mechanisms underlying the persistence of residual leukemia cells in TKI responders are the extrinsic equivalent of the intrinsic mechanisms that drive resistance in patients with primary or secondary TKI resistance. Within this conceptual framework of BCR–ABL1 independent resistance, we have experimentally implicated STAT3 as a critical signaling node that integrates extrinsic and intrinsic survival signals to promote TKI resistance. My personal goal is to push the limits of TKI-based therapy of CML to the point where a majority of patients will be cured with drug therapy.