Janet Davison Rowley (1925–2013)

The scientific community has lost one of its giants, whose work laid the foundation for modern cancer genetic research and a new paradigm for precision oncology, namely targeted therapy. The rest of the world has lost an extraordinary spirit who, as a mentor, mother, colleague, friend, and humanitarian inspired those around her to be better. Janet D. Rowley, M.D., died on December 17, 2013, from complications of ovarian cancer. Speaking about her own cancer experience as recently as November when she accepted an award from the University of Chicago Cancer Research Foundation, Janet said, “Cancer can be cured if we work hard enough.” It was that type of resolve and commitment that dictated her work and every other facet of her life.Janet RowleyView Large Image | View Hi-Res Image | Download PowerPoint SlideJanet was born April 5, 1925, in New York City, but before her second birthday, her family moved to Chicago, where she would live for most of her life. At only 15, she earned a scholarship to begin coursework at the University of Chicago. At 19 years of age, she applied to medical school at the University of Chicago, but was forced to delay a year because the quota for women (three) that year was filled. Janet married one of her classmates, Donald A. Rowley, M.D., the day after medical school graduation. When Janet worked as a physician at a clinic for children with mental retardation in Chicago, she was first exposed to cytogenetics and the astounding discovery that Down syndrome was the result of three copies of chromosome 21. When Don accepted a sabbatical appointment in Oxford, England in 1961, Janet secured a special postdoctoral fellowship from the National Institutes of Health and turned to Marco Fraccaro at the Medical Research Council Unit on Genetics in Headington, Oxford, to learn cytogenetics. It was then that she recalled cutting out the photographed chromosomes from metaphase cells, placing them on the dining room table, and ensuring that her young boys did not cough, sneeze, or otherwise disturb her carefully arranged karyotypes. This work catalyzed Janet’s passion for research, so much so that she decided not to return to the clinic. It also allowed her to have a flexible schedule to raise her boys.Upon returning to Chicago in 1962, she negotiated with Dr. Leon O. Jacobson, a hematologist at the University of Chicago, to use a photomicroscope and 3 ft of bench space to establish her research program on a part-time basis. She began to analyze the karyotypes of some of Dr. Jacobson’s patients and published a paper describing chromosome abnormalities in preleukemia. She later learned chromosome banding upon a return visit to Oxford in 1970. At that time, many hematologists and other scientists were not convinced about the importance of chromosome abnormalities, especially translocations, essentially converting Janet into an early “crusader for cytogenetics.”Early in 1972, she studied the cells of a patient with acute myeloid leukemia (AML) and identified a chromosome abnormality as a reciprocal translocation between chromosomes 8 and 21. At that time, she also had data that the Philadelphia chromosome (Ph), originally described in 1960 as a small deleted chromosome by Nowell and Hungerford, might be a translocation as well. In June 1973, Janet published the landmark paper that described the finding of a translocation between the long arms of chromosomes 9 and 22 in bone marrow cells from each of nine consecutive patients with chronic myelogenous leukemia (CML). The chromosomal translocations that Janet discovered in AML and CML are the first two recurring translocations in any human cancer; she went on to identify many other recurring abnormalities.A decade later, as cellular oncogenes were cloned and mapped to human chromosomes, Janet recognized that their chromosome location correlated with the breakpoints of the recurring translocations, and she proposed that the function of cellular oncogenes was altered as a result of chromosomal abnormalities, leading to uncontrolled proliferation. Over the ensuing years, many translocation breakpoints were cloned and the involved oncogenes were identified, thus ending her decades-long crusade to convince other physicians and scientists that chromosomal abnormalities in tumors were more than irrelevant epiphenomena that occurred as a result, rather than the cause, of the malignant phenotype.One of Janet’s greatest legacies is that she helped promote the understanding that cancer is not one disease, but many. Decades before the era of genomic profiling, her work, and that of her colleagues, led to the recognition that chromosome abnormalities were associated with distinct subtypes of leukemia and lymphoma and had prognostic significance. “Janet Rowley’s work established that cancer is a genetic disease,” said Mary-Claire King, professor of genome sciences and medicine at the University of Washington School of Medicine. “She demonstrated that mutations in critical genes lead to specific forms of leukemia and lymphoma and that one can determine the form of cancer present in a patient directly from the genetic changes in the cancer. We are still working from her paradigm.”It was Janet’s early work on the t(9;22) in CML that has culminated in the most successful example of targeted therapy to date—an approach that has revolutionized how genetic profiles of tumors are utilized in clinical care. Although it took many years after the breakpoint was mapped and the BCR-ABL1 fusion was identified, Imatinib, as well as second- and third-generation ABL1 tyrosine kinase inhibitors, have become standard therapy for patients with newly diagnosed CML, thereby changing the natural history of this disease.To elucidate how other translocations drove the cancer phenotype, Janet’s group cloned a number of translocation breakpoints. Further, her laboratory cloned the gene at the breakpoint of the common translocations of 11q23 that she called MLL, for myeloid-lymphoid leukemia (now known as KMT2A). This work resulted in the cloning of almost 75 MLL translocation partner genes, molecular detection of MLL leukemias, and, ultimately, the emergence of research on lysine methyltransferases in cancer. True to the spirit of innovation, Janet turned her attention in later years to defining the biological features of human leukemia by gene and microRNA expression profiling. To facilitate all of this work, as well as that of her colleagues around the globe, she organized a series of International Workshops that provided the clinical data and cytogenetic expertise to transform and advance the field of cancer genetics.We recently celebrated the 40th anniversary of her key discovery of recurring translocations, and she has been acknowledged for her contributions with some of the most prestigious award in biomedical research, including, in 2009, the Presidential Medal of Freedom. At that ceremony, President Obama noted, “All of us have been touched in some way by cancer, including my family—and so we can all be thankful that what began as a hobby became a life’s work for Janet.”Janet’s passion for her hobby and life’s work was infectious, and she gladly passed it along to the countless scientists and cytogeneticists whom she mentored and trained, including one of the authors (M.M.L.). She was especially supportive of female physicians and scientists and served as a role model for those who followed in her footsteps. She was extremely proud of raising her family, and she often commented on how she did not do anything very remarkable in her career until well into her 40s. Likewise, she attributed her accomplishments to good luck and timing. Clearly, humility and graciousness were qualities ascribed to Janet. She once said, “Looking down a microscope at banded chromosomes is not rocket science. If I had not found it, someone else would have.” Perhaps that is true, but it was Janet’s perseverance, her attention to detail, and some serendipity that secured her place in cancer research history. In recent years, she was also a vocal advocate for biomedical research, serving on the President’s Council on Bioethics and National Cancer Legislation Advisory Committee. She was concerned that the type of work that she did, so called “observation-driven research,” did not have a place in the “hypothesis-driven” science that is currently funded. Janet was also certain that the type of success that she had in her illustrious career would not have been possible today, underscoring her view that scientists need support, freedom, and creativity to address the critical questions.Janet Rowley’s career and legion of trainees are her enduring legacy to her belief that the ultimate goal of research is to benefit patients and improve human life. She leaves behind a scientific community and colleagues that will sorely miss her enthusiasm and passion for scientific advancement. Janet is survived by three of her four sons, who also lost their father Don last year, and five grandchildren.