JAK2 V617F 10 Years Later: Dr. Dameshek's Prophecy Fulfilled

For more than a century, clinicians have recognized myeloproliferative neoplasms (MPNs) as disorders that are characterized by expansion of different myeloid lineages, with important clinical sequelae. However, the seminal insight into these diseases came when Dr. William Dameshek wrote in an editorial in Blood that MPNs share specific clinical features including thrombosis, bleeding, and an increased risk of progression to leukemia.¹  This critical insight led to the classification of the different MPNs as a set of clinically related myeloid malignancies. However, his prescience did not stop there; he hypothesized that MPN were caused by an “undiscovered stimulus” and implored the field to investigate the biologic basis of the different MPNs. Although it took more than 50 years, 2005 marked the year that the field began realizing his vision.Over a span of just a few weeks in the spring of 2005, four different groups published their findings on the identification of the somatic JAK2 V617F mutation in 90 percent of patients with polycythemia vera (PV) and in approximately 50 percent of patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF).^2-5  The approaches used by each group were quite distinct. Dr. William Vainchenker’s group used elegant functional studies and biochemistry to implicate the JAK2 signaling pathway in MPN proliferation. Dr. Radek Skoda and colleagues mapped the region of 9q24 uniparental disomy⁶ to pinpoint JAK2 mutations, and Dr. Tony Green and colleagues investigated key signaling pathways for somatic mutations in MPN patient samples. Our collaborative efforts employed a novel ascertainment protocol to capture MPN samples, followed by high-throughput tyrosine kinome sequencing to uncover the JAK2 V617F allele. Although the approaches were different, the results were the same, and we all realized the importance of this discovery and its potential impact.At the time, the field rapidly moved to translate this discovery into the clinical setting, and many of us believed it would have major implications for the diagnosis and therapy of PV, ET, and MF. This has indeed turned out to be the case. JAK2 molecular testing is now an essential aspect of the diagnosis of the different MPNs, with mutational testing for JAK2 V617F being the standard of care worldwide. However, there have been many surprises along the way since the discovery of JAK2 V617F. It has taken almost a decade to identify most of the somatic mutations that govern JAK2 V617F–negative MPN, including JAK2 exon 12 mutations in PV⁷ and thrombopoietin receptor (MPL) mutations ET and PMF.⁸  More recently, two groups identified recurrent mutations in the calreticulin (CALR) gene in the majority of JAK2/MPL–wild-type MPN patients.^9,10  Although there are still many questions that remain, our knowledge of the genetic basis of the different MPNs has increased dramatically since 2005, and we now have a molecular framework of the different MPNs, which can inform mechanistic and translational studies. More importantly, the discovery of JAK2 mutations suggested that JAK-STAT signaling was a central feature of MPN pathogenesis, which led to the development and approval of the JAK1/JAK2 inhibitor ruxolitinib for patients with MF, and more recently for PV patients with resistance or intolerance to hydroxyurea.¹¹ We recognize there is still much to learn. At the time of the discovery of JAK2, we hypothesized that subsequent genomic studies would elucidate the basis for phenotypic pleiotropy of JAK2-mutant MPN; however we still do not know why JAK2 mutations are observed in a spectrum of different MPNs with varying clinical presentations and outcomes. Additionally, although the discovery of JAK2 mutations has led to the clinical development of JAK kinase inhibitors, there remains a pressing need to understand the basis for JAK2 inhibitor sensitivity and resistance, and to develop novel therapeutic approaches and combination strategies to improve patient outcomes. Toward that end, we have been able to identify bypass mechanisms by which JAK2 can be activated in JAK2-inhibitor “persistent” cells and patient samples. This has led us to investigate whether novel therapeutic approaches, including HSp90 inhibitors and type II JAK2 inhibitors can be used to improve JAK2 targeting and to increase therapeutic efficacy. We are confident that these challenges will be solved by our field.However, in our view, the discovery of the JAK2 V617F mutation has meant much more. In 2004, MPN investigators presented their work at the ASH annual meeting in a single Tuesday morning simultaneous oral session with no more than 50 people in the room. Now, thousands of annual meeting attendees can hear about developments in MPNs, including numerous preclinical models, genomic studies, and clinical trials of novel agents in various stages of development. In short, JAK2 V617F was a disruptive breakthrough that re-energized the field and ushered in the modern era of MPN biology. On a personal note, this discovery was the impetus for one of the authors to start his career (R.L.), and there are many other investigators whose careers were accelerated, inspired, and based on this seminal finding. If not for the vision and support of the senior MPN investigators who led these initial efforts, we would not have a vibrant field of innovative and collaborative researchers and clinicians who continue to make discoveries that elucidate biology and help MPN patients on a daily basis.

JAK2 V617F represented a key finding at a critical time that helped to usher in the modern era of precision medicine. We now take for granted that molecular genetic studies can be used to diagnose cancer patients, to risk stratify patients into different subsets, and to guide the development and use of molecularly targeted therapies in the clinic. The identification of JAK2 V617F provided the impetus for the next decade of genomic insights in nearly all human malignancies. We are at a different place now because of this discovery; it has changed the lives of scientists, physicians, and most importantly, patients, in countless ways.