Baton Pass No. 1 The researchers
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y 1986, Michelle M. Le Beau, PhD, now the Arthur and Marian Edelstein Professor of Medicine and director of the University of Chicago Medicine Comprehensive Cancer Center, who had trained with Rowley, was leading the effort. Her team had 62 patients with treatment-triggered AML and limited the search to the long arm of chromosome 7, known as 7q. Most of those patients had received alkylating agents, chemotherapy drugs that bind to DNA and interfere with replication. By the mid-1990s, new tools were helping the team narrow the focus. They now had hundreds of patients. Most of the samples were missing all of chromosome 7, but 81 had lost only part of chromosome 7. This helped focus the search to a region known as 7q22. Still, this smaller region included more than 2 million base pairs, enough to contain 50 genes. Plus, there was a new wrinkle: in no patient were both versions of a specific gene in the target region abnormal. There always seemed to be one functional copy. Scientists had learned, however, that loss of just one copy of a gene may be damaging enough. The remaining copy could be normal but unable to meet the demand. Geneticists call this haploinsufficiency.
Baton Pass No. 2
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n 2009, Megan McNerney, MD’07, PhD’05, doing a residency in clinical pathology and working in White’s lab in the IGSB, pulled together collaborators to identify the gene whose loss “malfunction” drives the loss of 7q22. McNerney first produced higher-resolution data from 35 leukemia patients with focused abnormalities on chromosome 7. Working with other IGSB scientists, she then combed through region 7q22, and a gene known to regulate many other genes stood out. This gene, CUX1, was expressed at low levels in patient samples with loss of one copy. uchospitals.edu/midway
Janet D. Rowley, LAB’42, PhB’44, SB’46, MD’48 In 1973, Rowley describes two patients with recurrent blood diseases whose bone marrow cells showed “deficiencies” involving chromosome 7. The search is on.
Michelle M. Le Beau, PhD By 1986, Le Beau, who trained with Rowley, is leading the investigation. Over the next decade, Le Beau and colleagues narrow the focus to a region known as 7q22.
So McNerney, collaborating with another White lab postdoctoral student, Xiaoyue Wang, PhD, created fruit flies with only a single copy of CUX1. Samples from the flies’ blood revealed abnormalities characteristic of leukemia. Next, working with John M. Cunningham, MD, professor of pediatrics, physiology, and stem cell research, chief of pediatric hematology/oncology and director of hematopoietic stem cell transplantation at the University of Chicago Medicine Comer Children’s Hospital, they developed mice whose blood-forming cells were deficient in CUX1. These mice quickly developed features of leukemia. There may be other genes in the commonly deleted sequence “that play a role in disease pathogenesis,” the study authors wrote, but “this is the first biological confirmation of a haploinsufficient myeloid tumor suppressor gene on chromosome band 7q22. … Changes in CUX1 levels may have important phenotypes during hematopoiesis and deleterious consequences when altered.” The study was published in February in Blood.
Megan McNerney, MD’07, PhD’05 Beginning in 2009, McNerney and team comb through 7q22 and discover a haploinsufficient myeloid tumor suppressor gene implicated in therapy-related leukemia.
“ The identification of this gene underscores the value of the integrated approach we are trying to promote in the IGSB,” White said. “By harnessing next generation sequencing technology and advanced algorithms to identify the gene, then moving to animal model systems and complementary patient data to validate the discovery, Dr. McNerney and the team she worked with have done an incredible job of solving a difficult long-standing puzzle in a short amount of time. Her experience here is a model for what we want clinical fellows working in the IGSB to achieve.” The discovery also presents clinical options. “If we learn how CUX1 is regulated, we could tweak its expression or hit the pathway downstream or find ways to influence its activity,” Le Beau said. “We may also find ways to use CUX1 testing to predict who is at risk prior to the initial treatment and to change the therapy for those patients.” Le Beau notes that this integrated approach to tackling leukemia was made possible by funding from the Cancer Research Foundation. MEDICINE ON THE MIDWAY
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