Christina L Boulton
- Associate Professor, Orthopaedic Surgery - (Clinical Scholar Track)
Dr. Boulton is an Associate Professor of Orthopaedic Surgery in the Department of Orthopaedic Surgery at The University of Arizona College of Medicine where she has been a faculty member since June of 2016.
Before relocating to Tucson she was a member of the orthopaedic faculty at the University of Maryland School of Medicine specializing in orthopaedic traumatology. Her practice involved serving patients at the R Adams Cowley Shock Trauma Center (Level-I Trauma Center) and the Prince George’s Hospital Center (Level-II, Regional Trauma Center) from 2011-2016.
Dr. Boulton completed her medical degree at the Harvard-MIT Health Sciences & Technology (HST) program at Harvard Medical School in 2005. During medical school she was awarded a Howard Hughes Medical Institute Research Fellowship and the Karin Grunebaum Cancer Research Foundation Fellowship for her research on mouse models of leukemia. She went on to complete an orthopaedic surgical residency at the Harvard Combined Orthopaedic Residency Program where she served as an administrative Chief Resident. Following residency she performed a one year orthopaedic trauma fellowship at the R Adams Cowley Shock Trauma Center-University of Maryland Medical Center in Baltimore, MD.
She is very passionate about resident education. Previously, she was a member of the University of Maryland orthopaedic residency program education committee and has served as the Associate Residency Program Director for the University of Arizona orthopaedic residency in Tucson from 2017-2022. Each year she serves as an invited faculty member at numerous AO resident courses across the country.
Dr. Boulton is board certified by the American Board of Orthopaedic Surgery and is a member of the American Association of Orthopaedic Surgeons (AAOS), the Orthopaedic Trauma Association (OTA), AOTrauma and the Arizona Orthopaedic Society. She maintains a busy full-time clinical practice at Banner University Medical Center focusing primarily on orthopaedic traumatology, but also has interest in disorders of the foot and ankle as well as treatment of post-traumatic conditions such as limb deformity, limb length discrepancy, chronic osteomyelitis and post-traumatic arthritis.
- M.D. Medical Doctor
- Harvard Medical School, Boston, Massachusetts, United States
- B.S. Genetics and English Literature
- University of California, Tucson, Arizona, United States
- University of Maryland School of Medicine (2011 - 2016)
- University of Maryland Medical Center (2010 - 2011)
- Massachusetts General Hospital, Orthopaedic Surgery (2006 - 2010)
- Massachusetts General Hospital, General Surgery (2005 - 2006)
- Resident Teaching Award "Hands Off"
- Summer 2022
- Educator of the Year
- The Department of Orthopaedic Surgery, The University of Arizona, Summer 2017
Licensure & Certification
- Maryland Medical License, Maryland Board of Physicians (2011)
- Arizona Medical License, Arizona Medical Board (2016)
- USMLE Boards Part 1, The American Board of Orthopaedic Surgery (2010)
- USMLE Boards Part II, The American Board of Orthopaedic Surgery (2013)
Trauma, complex fracture care, nonunion/malunion correction.
Trauma, complex fracture care, nonunion/malunion correction.
No activities entered.
- Ryan, S. P., Boulton, C. L., & O'toole, R. V. (2013). Open Diaphyseal Tibia Fractures. In Orthopedic Traumatology: An Evidence Based Approach. Springer, New York, NY. doi:10.1007/978-1-4614-3511-2_21More infoMI is a 24-year-old male who presents to the emergency department with a chief complaint of left leg pain after being thrown off of his ATV while riding in woods. He denies any other injuries or pain. On primary survey he demonstrates a GCS of 15, a patent airway, and is hemodynamically stable. On secondary survey he demonstrates a gross deformity to the left leg with a large open wound and exposed bone. His past medical history is consistent with depression. His only medication is Lexapro® (escitalopram, a selective serotonin reuptake inhibitor) and he has no allergies.
- Slobogean, G. P., Sciadini, M. F., Pollak, A. N., O'toole, R. V., O'hara, N. N., Nascone, J. W., Manson, T. T., Lebrun, C. T., & Boulton, C. L. (2022). Open reduction and internal fixation alone versus open reduction and internal fixation plus total hip arthroplasty for displaced acetabular fractures in patients older than 60 years: A prospective clinical trial.. Injury, 53(2), 523-528. doi:10.1016/j.injury.2021.09.048More infoThe optimal treatment of elderly patients with an acetabular fracture is unknown. We conducted a prospective clinical trial to compare functional outcomes and reoperation rates in patients older than 60 years with acetabular fracture treated with open reduction and internal fixation (ORIF) alone versus ORIF plus concomitant total hip arthroplasty (ORIF + THA). Our hypothesis was that patients who had ORIF + THA would have better patient reported outcomes and lower reoperation rates postoperatively..Inclusion criteria were patients older than 60 years with acetabular fracture plus at least one of three fracture characteristics: dome impaction, femoral head fracture, or posterior wall component. Eligible patients were operative candidates based on fracture displacement, ambulatory status, and physiological appropriateness. Patients received either ORIF alone or ORIF + THA (accomplished at same surgery through same incision). Outcome measurements included Western Ontario and McMaster Universities Osteoarthritis Index hip score, Short Form 36, Harris Hip Score, and Patient Satisfaction Questionnaire Short Form scores. Additionally, patients were monitored for any unplanned reoperation within 2 years..Forty-seven of 165 eligible patients with an average age of 70.7 years were included. The mean Harris Hip Score difference favored ORIF + THA (mean difference, 12.3, [95% confidence interval (CI), -0.3 to 24.9, p = 0.07]). No clinically important differences were detected in any other validated outcome score or patient satisfaction score 1 year after surgery. ORIF + THA decreased the absolute risk of reoperation by 28% (95% CI, 13% to 44%, p < 0.01). No postoperative hip dislocation occurred in either group..In patients older than 60 years with an operative displaced acetabular fracture with specific fracture features (dome impaction, femoral head fracture, or posterior wall component), treatment with ORIF + THA resulted in fewer reoperations than treatment with ORIF alone. No differences in patient satisfaction and other validated outcome measures were detected.
- , M. E., O'Toole, R. V., Joshi, M., Carlini, A. R., Murray, C. K., Allen, L. E., Huang, Y., Scharfstein, D. O., O'Hara, N. N., Gary, J. L., Bosse, M. J., Castillo, R. C., Bishop, J. A., Weaver, M. J., Firoozabadi, R., Hsu, J. R., Karunakar, M. A., Seymour, R. B., Sims, S. H., , Churchill, C., et al. (2021). Effect of Intrawound Vancomycin Powder in Operatively Treated High-risk Tibia Fractures: A Randomized Clinical Trial. JAMA surgery, 156(5), e207259.More infoDespite the widespread use of systemic antibiotics to prevent infections in surgically treated patients with fracture, high rates of surgical site infection persist.
- Manson, T. T., Slobogean, G. P., Nascone, J. W., Sciadini, M. F., LeBrun, C. T., Boulton, C. L., O'Hara, N. N., Pollak, A. N., & O'Toole, R. V. (2021). Open reduction and internal fixation alone versus open reduction and internal fixation plus total hip arthroplasty for displaced acetabular fractures in patients older than 60 years: A prospective clinical trial. Injury.More infoThe optimal treatment of elderly patients with an acetabular fracture is unknown. We conducted a prospective clinical trial to compare functional outcomes and reoperation rates in patients older than 60 years with acetabular fracture treated with open reduction and internal fixation (ORIF) alone versus ORIF plus concomitant total hip arthroplasty (ORIF + THA). Our hypothesis was that patients who had ORIF + THA would have better patient reported outcomes and lower reoperation rates postoperatively.
- Gitajn, I. L., Reider, L., Scharfstein, D. O., OʼToole, R. V., Bosse, M. J., Castillo, R. C., Jevsevar, D. S., Pollak, A. N., & , M. (2020). Variability in Discharge Disposition Across US Trauma Centers After Treatment for High-Energy Lower Extremity Injuries. Journal of orthopaedic trauma, 34(3), e78-e85.More infoTo evaluate the association between patient- and center-level characteristics and discharge to an inpatient facility versus home after treatment for lower extremity trauma, as well as examine the variability in discharge disposition across clinical centers after controlling for these factors.
- Hale, D., Marvel, D., Wells, J., & , P. I. (2020). What's Important: Patient Engagement in Research. The Journal of bone and joint surgery. American volume, 102(20), 1836-1838.
- Sprague, S., Scott, T., Dodds, S., Pogorzelski, D., McKay, P., Harris, A. D., Wood, A., Thabane, L., Bhandari, M., Mehta, S., Gaski, G., Boulton, C., Marcano-Fernández, F., Guerra-Farfán, E., Hebden, J., O'Hara, L. M., Slobogean, G. P., & , P. I. (2020). Cluster identification, selection, and description in cluster randomized crossover trials: the PREP-IT trials. Trials, 21(1), 712.More infoIn cluster randomized crossover (CRXO) trials, groups of participants (i.e., clusters) are randomly allocated to receive a sequence of interventions over time (i.e., cluster periods). CRXO trials are becoming more comment when they are feasible, as they require fewer clusters than parallel group cluster randomized trials. However, CRXO trials have not been frequently used in orthopedic fracture trials and represent a novel methodological application within the field. To disseminate the early knowledge gained from our experience initiating two cluster randomized crossover trials, we describe our process for the identification and selection of the orthopedic practices (i.e., clusters) participating in the PREP-IT program and present data to describe their key characteristics.
- Sprague, S., Scott, T., Dodds, S., Pogorzelski, D., McKay, P., Harris, A. D., Wood, A., Thabane, L., Bhandari, M., Mehta, S., Gaski, G., Boulton, C., Marcano-Fernández, F., Guerra-Farfán, E., Hebden, J., O'Hara, L. M., Slobogean, G. P., & , P. I. (2020). Correction to: Cluster identification, selection, and description in Cluster randomized crossover trials: the PREP-IT trials. Trials, 21(1), 821.More infoAn amendment to this paper has been published and can be accessed via the original article.
- , F. I., Slobogean, G. P., Sprague, S., Bzovsky, S., Heels-Ansdell, D., Thabane, L., Scott, T., & Bhandari, M. (2019). Fixation using alternative implants for the treatment of hip fractures (FAITH-2): design and rationale for a pilot multi-centre 2 × 2 factorial randomized controlled trial in young femoral neck fracture patients. Pilot and feasibility studies, 5, 70.More infoFemoral neck fractures in patients ≤ 60 years of age are often very different injuries compared to low-energy, hip fractures in elderly patients and are difficult to manage because of inherent problems associated with high-energy trauma mechanisms and increased functional demands for recovery. Internal fixation, with multiple cancellous screws or a sliding hip screw (SHS), is the most common treatment for this injury in young patients. However, there is no clinical consensus regarding which surgical technique is optimal. Additionally, there is compelling rationale to use vitamin D supplementation to nutritionally optimize bone healing in young patients. This pilot trial will determine feasibility and provide preliminary clinical data for a larger definitive trial.
- Sanal, H. T., Boulton, C., Neyisci, C., Erdem, Y., & Lowe, J. (2019). Imaging of Pelvic and Femoral Fixation Hardware: Normal Findings and Hardware Failure. Seminars in musculoskeletal radiology, 23(2), e1-e19.More infoGood outcomes following treatment of pelvic ring injuries, acetabular fractures, and femur fractures rely on restoration of native pelvic or limb alignment, anatomical reduction and rigid stability of articular fractures, and early postoperative mobilization. Multiple surgical approaches, reduction aids, and orthopaedic implants are available to stabilize these fractures. Despite best practices, complications including hardware failure, nonunions, malunions, and infections occur. This article discusses common fracture classification systems, implants, and imaging findings associated with unwanted complications in fractures of the pelvis, acetabulum, and femur.
- Shah, J., Titus, A. J., O'Toole, R. V., Sciadini, M. F., Boulton, C., Castillo, R., Breazeale, S., Schoonover, C., Berger, P., & Gitajn, I. L. (2019). Are geriatric patients who sustain high-energy traumatic injury likely to return to functional independence?. Journal of orthopaedic trauma.More infoTo evaluate physical function and return to independence of geriatric trauma patients, to compare physical function outcomes of geriatric patients who sustained high-energy trauma with that of those who sustained low-energy trauma, and to identify predictors of physical function outcomes.
- Matuszewski, P. E., Boulton, C. L., & O'Toole, R. V. (2016). Orthopaedic trauma patients and smoking: Knowledge deficits and interest in quitting. Injury, 47(6), 1206-11.More infoSmoking is associated with increased complications in fracture care. Smoking cessation has a positive impact on outcomes. It is unknown whether orthopaedic trauma patients understand the ill effects of smoking on fracture care and whether knowledge can improve cessation interest. We hypothesized that (1) smokers less fully understand the negative effects of smoking than do nonsmokers, (2) an increased proportion of orthopaedic trauma patients are further in the process of change to quit smoking, (3) increased knowledge predicts increased readiness to quit, and (4) minimal education through a survey can improve interest in smoking cessation.
- Mir, H. R., Boulton, C. L., Russell, G. V., & Archdeacon, M. (2016). Lower Extremity Fracture Reduction: Tips, Tricks, and Techniques So That You Leave the Operating Room Satisfied. Instructional course lectures, 65, 25-39.More infoIt can be challenging for surgeons to obtain proper alignment and to create stable constructs for the maintenance of many lower extremity fractures until union is achieved. Whether lower extremity fractures are treated with plates and screws or intramedullary nails, there are numerous pearls that may help surgeons deal with these difficult injuries. Various intraoperative techniques can be used for lower extremity fracture reduction and stabilization. The use of several reduction tools, tips, and tricks may facilitate the care of lower extremity fractures and, subsequently, improve patient outcomes.
- Boulton, C. L., & Pollak, A. N. (2015). Special topic: Ipsilateral femoral neck and shaft fractures--does evidence give us the answer?. Injury, 46(3), 478-83.More infoIpsilateral fractures of the femoral neck and shaft are rare, high-energy injuries that typically occur in young polytrauma patients. The associated fracture of the neck is often vertical in nature and is more frequently non-displaced than in isolated femoral neck fractures. Historically the diagnosis of an associated femoral neck fracture was delayed or missed in approximately one third of cases. Studies have shown that detection can be significantly improved with the implementation of a protocolized approach to hip imaging in all patients with femoral shaft fractures. Prompt recognition of an associated femoral neck fracture allows for timely stabilization and may decrease the risks of non-union and avascular necrosis. In contrast, failure to recognize a non-displaced or minimally displaced associated neck fracture prior to fixation of the shaft can lead to displacement, a decrease in neck fixation options, a technically challenging secondary procedure and increased risk of long-term sequelae. A vast array of treatment strategies have been described for this combined injury. Published options range from spica casting to open reduction and internal fixation of both fractures and include almost all conceivable combinations in between. While timely surgical stabilization is now universally recommended for both shaft and neck, no consensus exists as to the most appropriate method of fixation for either fracture. Most authors recommend prompt, but not emergent, surgery with priority given to anatomic reduction and stabilization of the neck fracture by either closed or open methods. Fixation of the shaft fracture follows as patient condition allows. The rare nature of this injury makes it very challenging to study and most published series' are retrospective with very small sample sizes. In short, no scientificallycompelling study is available to definitively support any one implant choice or method of stabilzation over another for the treatment of associated fractures of the femoral neck and shaft.
- Eagan, M., Kim, H., Manson, T. T., Gary, J. L., Russell, J. P., Hsieh, A. H., O'Toole, R. V., & Boulton, C. L. (2015). Internal anterior fixators for pelvic ring injuries: Do monaxial pedicle screws provide more stiffness than polyaxial pedicle screws?. Injury, 46(6), 996-1000.More infoLittle is known about the mechanical properties of internal anterior fixators (known as INFIX), which have been proposed as subcutaneous alternatives to traditional anterior external fixators for pelvic ring disruptions. We hypothesised that INFIX has superior biomechanical performance compared with traditional external fixators because the distance from the bar to the bone is reduced.
- Boulton, C. L., Kim, H., Shah, S. B., Ryan, S. P., Metzger, T. A., Hsieh, A. H., & O'Toole, R. V. (2014). Do locking screws work in plates bent at holes?. Journal of orthopaedic trauma, 28(4), 189-94.More infoTo assess whether plate bending at a hole significantly changes the biomechanical properties of a locked screw.
- Rodriguez, E. K., Boulton, C., Weaver, M. J., Herder, L. M., Morgan, J. H., Chacko, A. T., Appleton, P. T., Zurakowski, D., & Vrahas, M. S. (2014). Predictive factors of distal femoral fracture nonunion after lateral locked plating: a retrospective multicenter case-control study of 283 fractures. Injury, 45(3), 554-9.More infoReported initial success rates after lateral locked plating (LLP) of distal femur fractures have led to more concerning outcomes with reported nonunion rates now ranging from 0 to 21%. Reported factors associated with nonunion include comorbidities such as obesity, age and diabetes. In this study, our goal was to identify patient comorbidities, injury and construct characteristics that are independent predictors of nonunion risk in LLP of distal femur fractures; and to develop a predictive algorithm of nonunion risk, irrespective of institutional criteria for clinical intervention variability.
- Boulton, C. L., Salzler, M., & Mudgal, C. S. (2010). Intramedullary cannulated headless screw fixation of a comminuted subcapital metacarpal fracture: case report. The Journal of hand surgery, 35(8), 1260-3.More infoThis case report describes an alternative technique for the fixation of displaced comminuted subcapital fractures of the metacarpal with limited distal bone stock. Using a cannulated headless screw as an intramedullary device placed through the articular surface, we were able to secure proximal and distal bone purchase without excessive soft tissue stripping or disruption of the fracture hematoma. This technique allows early rehabilitation, and our patient went on to uneventful healing with excellent functional results.
- Lee, B. H., Williams, I. R., Anastasiadou, E., Boulton, C. L., Joseph, S. W., Amaral, S. M., Curley, D. P., Duclos, N., Huntly, B. J., Fabbro, D., Griffin, J. D., & Gilliland, D. G. (2005). FLT3 internal tandem duplication mutations induce myeloproliferative or lymphoid disease in a transgenic mouse model. Oncogene, 24(53), 7882-92.More infoActivating FMS-like tyrosine kinase 3 (FLT3) mutations have been identified in approximately 30% of patients with acute myelogenous leukemia (AML), and recently in a smaller subset of patients with acute lymphoblastic leukemia (ALL). To explore the in vivo consequences of an activating FLT3 internal tandem duplication mutation (FLT3-ITD), we created a transgenic mouse model in which FLT3-ITD was expressed under the control of the vav hematopoietic promoter. Five independent lines of vav-FLT3-ITD transgenic mice developed a myeloproliferative disease with high penetrance and a disease latency of 6-12 months. The phenotype was characterized by splenomegaly, megakaryocytic hyperplasia, and marked thrombocythemia, but without leukocytosis, polycythemia, or marrow fibrosis, displaying features reminiscent of the human disease essential thrombocythemia (ET). Clonal immature B- or T-lymphoid disease was observed in two additional founder mice, respectively, that could be secondarily transplanted to recipient mice that rapidly developed lymphoid disease. Treatment of these mice with the FLT3 tyrosine kinase inhibitor, PKC412, resulted in suppression of disease and a statistically significant prolongation of survival. These results demonstrate that FLT3-ITD is capable of inducing myeloproliferative as well as lymphoid disease, and indicate that small-molecule tyrosine kinase inhibitors may be an effective treatment for lymphoid malignancies in humans that are associated with activating mutations in FLT3.
- Mohi, M. G., Williams, I. R., Dearolf, C. R., Chan, G., Kutok, J. L., Cohen, S., Morgan, K., Boulton, C., Shigematsu, H., Keilhack, H., Akashi, K., Gilliland, D. G., & Neel, B. G. (2005). Prognostic, therapeutic, and mechanistic implications of a mouse model of leukemia evoked by Shp2 (PTPN11) mutations. Cancer cell, 7(2), 179-91.More infoThe SH2-containing tyrosine phosphatase Shp2 (PTPN11) is required for growth factor and cytokine signaling. Germline Shp2 mutations cause Noonan Syndrome (NS), which is associated with increased risk of juvenile myelomonocytic leukemia (JMML). Somatic Shp2 mutations occur in sporadic JMML and other leukemias. We found that Shp2 mutants associated with sporadic leukemias transform murine bone marrow cells, whereas NS mutants are less potent in this assay. Transformation requires multiple domains within Shp2 and the Shp2 binding protein Gab2, and is associated with hyperactivation of the Erk, Akt, and Stat5 pathways. Mutant Shp2-transduced BM causes a fatal JMML-like disorder or, less commonly, lymphoproliferation. Shp2 mutants also cause myeloproliferation in Drosophila. Mek or Tor inhibitors potently inhibit transformation, suggesting new approaches to JMML therapy.
- Laurencon, A., Orme, C. M., Peters, H. K., Boulton, C. L., Vladar, E. K., Langley, S. A., Bakis, E. P., Harris, D. T., Harris, N. J., Wayson, S. M., Hawley, R. S., & Burtis, K. C. (2004). A large-scale screen for mutagen-sensitive loci in Drosophila. Genetics, 167(1), 217-31.More infoIn a screen for new DNA repair mutants, we tested 6275 Drosophila strains bearing homozygous mutagenized autosomes (obtained from C. Zuker) for hypersensitivity to methyl methanesulfonate (MMS) and nitrogen mustard (HN2). Testing of 2585 second-chromosome lines resulted in the recovery of 18 mutants, 8 of which were alleles of known genes. The remaining 10 second-chromosome mutants were solely sensitive to MMS and define 8 new mutagen-sensitive genes (mus212-mus219). Testing of 3690 third chromosomes led to the identification of 60 third-chromosome mutants, 44 of which were alleles of known genes. The remaining 16 mutants define 14 new mutagen-sensitive genes (mus314-mus327). We have initiated efforts to identify these genes at the molecular level and report here the first two identified. The HN2-sensitive mus322 mutant defines the Drosophila ortholog of the yeast snm1 gene, and the MMS- and HN2-sensitive mus301 mutant defines the Drosophila ortholog of the human HEL308 gene. We have also identified a second-chromosome mutant, mus215(ZIII-2059), that uniformly reduces the frequency of meiotic recombination to
- Mohi, M. G., Boulton, C., Gu, T. L., Sternberg, D. W., Neuberg, D., Griffin, J. D., Gilliland, D. G., & Neel, B. G. (2004). Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs. Proceedings of the National Academy of Sciences of the United States of America, 101(9), 3130-5.More infoAbnormal protein tyrosine kinases (PTKs) cause many human leukemias. For example, BCR/ABL causes chronic myelogenous leukemia (CML), whereas FLT3 mutations contribute to the pathogenesis of acute myelogenous leukemia. The ABL inhibitor Imatinib (Gleevec, STI571) has remarkable efficacy for treating chronic phase CML, and FLT3 inhibitors (e.g., PKC412) show similar promise in preclinical studies. However, resistance to PTK inhibitors is a major emerging problem that may limit long-term therapeutic efficacy. Development of rational combination therapies will probably be required to effect cures of these and other neoplastic disorders. Here, we report that the mTOR inhibitor rapamycin synergizes with Imatinib against BCR/ABL-transformed myeloid and lymphoid cells and increases survival in a murine CML model. Rapamycin/Imatinib combinations also inhibit Imatinib-resistant mutants of BCR/ABL, and rapamycin plus PKC412 synergistically inhibits cells expressing PKC412-sensitive or -resistant leukemogenic FLT3 mutants. Biochemical analyses raise the possibility that inhibition of 4E-BP1 phosphorylation may be particularly important for the synergistic effects of PTK inhibitor/rapamycin combinations. Addition of a mitogen-activated protein kinase kinase inhibitor to rapamycin or rapamycin plus PTK inhibitor further increases efficacy. Our results suggest that simultaneous targeting of more than one signaling pathway required by leukemogenic PTKs may improve the treatment of primary and relapsed CML and/or acute myelogenous leukemia caused by FLT3 mutations. Similar strategies may be useful for treating solid tumors associated with mutant and/or overexpressed PTKs.
- Cools, J., Stover, E. H., Boulton, C. L., Gotlib, J., Legare, R. D., Amaral, S. M., Curley, D. P., Duclos, N., Rowan, R., Kutok, J. L., Lee, B. H., Williams, I. R., Coutre, S. E., Stone, R. M., DeAngelo, D. J., Marynen, P., Manley, P. W., Meyer, T., Fabbro, D., , Neuberg, D., et al. (2003). PKC412 overcomes resistance to imatinib in a murine model of FIP1L1-PDGFRα-induced myeloproliferative disease. Cancer cell, 3(5), 459-69.More infoFIP1L1-PDGFRalpha causes hypereosinophilic syndrome (HES) and is inhibited by the tyrosine kinase inhibitor imatinib (Gleevec). Imatinib is a potent inhibitor of ABL, ARG, PDGFRalpha, PDGFRbeta, and KIT and induces durable hematologic responses in HES patients. However, we observed relapse with resistance to imatinib as consequence of a T674I mutation in FIP1L1-PDGFRalpha, analogous to the imatinib-resistant T315I mutation in BCR-ABL. We developed a murine bone marrow transplant model of FIP1L1-PDGFRalpha-induced myeloproliferative disease to evaluate the efficacy of PKC412, an alternative inhibitor of PDGFRalpha, for the treatment of HES. PKC412 is effective for treatment of FIP1L1-PDGFRalpha-induced disease and of imatinib-induced resistance due to the T674I mutation. Our data establish PKC412 as molecularly targeted therapy for HES and other diseases expressing activated PDGFRalpha and demonstrate the potential of alternative kinase inhibitors to overcome resistance in target tyrosine kinases.
- Kelly, L. M., Kutok, J. L., Williams, I. R., Boulton, C. L., Amaral, S. M., Curley, D. P., Ley, T. J., & Gilliland, D. G. (2002). PML/RARalpha and FLT3-ITD induce an APL-like disease in a mouse model. Proceedings of the National Academy of Sciences of the United States of America, 99(12), 8283-8.More infoAcute promyelocytic leukemia (APL) cells invariably express aberrant fusion proteins involving the retinoic acid receptor alpha (RARalpha). The most common fusion partner is promyelocytic leukemia protein (PML), which is fused to RARalpha in the balanced reciprocal chromosomal translocation, t(15;17)(q22:q11). Expression of PML/RARalpha from the cathepsin G promoter in transgenic mice causes a nonfatal myeloproliferative syndrome in all mice; about 15% go on to develop APL after a long latent period, suggesting that additional mutations are required for the development of APL. A candidate target gene for a second mutation is FLT3, because it is mutated in approximately 40% of human APL cases. Activating mutations in FLT3, including internal tandem duplication (ITD) in the juxtamembrane domain, transform hematopoietic cell lines to factor independent growth. FLT3-ITDs also induce a myeloproliferative disease in a murine bone marrow transplant model, but are not sufficient to cause AML. Here, we test the hypothesis that PML/RARalpha can cooperate with FLT3-ITD to induce an APL-like disease in the mouse. Retroviral transduction of FLT3-ITD into bone marrow cells obtained from PML/RARalpha transgenic mice results in a short latency APL-like disease with complete penetrance. This disease resembles the APL-like disease that occurs with long latency in the PML/RARalpha transgenics, suggesting that activating mutations in FLT3 can functionally substitute for the additional mutations that occur during mouse APL progression. The leukemia is transplantable to secondary recipients and is ATRA responsive. These observations document cooperation between PML/RARalpha and FLT3-ITD in development of the murine APL phenotype.
- Kelly, L. M., Liu, Q., Kutok, J. L., Williams, I. R., Boulton, C. L., & Gilliland, D. G. (2002). FLT3 internal tandem duplication mutations associated with human acute myeloid leukemias induce myeloproliferative disease in a murine bone marrow transplant model. Blood, 99(1), 310-8.More infoFLT3 receptor tyrosine kinase is expressed on lymphoid and myeloid progenitors in the hematopoietic system. Activating mutations in FLT3 have been identified in approximately 30% of patients with acute myelogenous leukemia, making it one of the most common mutations observed in this disease. Frequently, the mutation is an in-frame internal tandem duplication (ITD) in the juxtamembrane region that results in constitutive activation of FLT3, and confers interleukin-3 (IL-3)-independent growth to Ba/F3 and 32D cells. FLT3-ITD mutants were cloned from primary human leukemia samples and assayed for transformation of primary hematopoietic cells using a murine bone marrow transplantation assay. FLT3-ITDs induced an oligoclonal myeloproliferative disorder in mice, characterized by splenomegaly and leukocytosis. The myeloproliferative phenotype, which was associated with extramedullary hematopoiesis in the spleen and liver, was confirmed by histopathologic and flow cytometric analysis. The disease latency of 40 to 60 days with FLT3-ITDs contrasted with wild-type FLT3 and enhanced green fluorescent protein (EGFP) controls, which did not develop hematologic disease (> 200 days). These results demonstrate that FLT3-ITD mutant proteins are sufficient to induce a myeloproliferative disorder, but are insufficient to recapitulate the AML phenotype observed in humans. Additional mutations that impair hematopoietic differentiation may be required for the development of FLT3-ITD-associated acute myeloid leukemias. This model system should be useful to assess the contribution of additional cooperating mutations and to evaluate specific FLT3 inhibitors in vivo.
- Kelly, L. M., Yu, J. C., Boulton, C. L., Apatira, M., Li, J., Sullivan, C. M., Williams, I., Amaral, S. M., Curley, D. P., Duclos, N., Neuberg, D., Scarborough, R. M., Pandey, A., Hollenbach, S., Abe, K., Lokker, N. A., Gilliland, D. G., & Giese, N. A. (2002). CT53518, a novel selective FLT3 antagonist for the treatment of acute myelogenous leukemia (AML). Cancer cell, 1(5), 421-32.More infoUp to 30% of acute myelogenous leukemia (AML) patients harbor an activating internal tandem duplication (ITD) within the juxtamembrane domain of the FLT3 receptor, suggesting that it may be a target for kinase inhibitor therapy. For this purpose we have developed CT53518, a potent antagonist that inhibits FLT3, platelet-derived growth factor receptor (PDGFR), and c-Kit (IC(50) approximately 200 nM), while other tyrosine or serine/threonine kinases were not significantly inhibited. In Ba/F3 cells expressing different FLT3-ITD mutants, CT53518 inhibited IL-3-independent cell growth and FLT3-ITD autophosphorylation with an IC(50) of 10-100 nM. In human FLT3-ITD-positive AML cell lines, CT53518 induced apoptosis and inhibited FLT3-ITD phosphorylation, cellular proliferation, and signaling through the MAP kinase and PI3 kinase pathways. Therapeutic efficacy of CT53518 was demonstrated both in a nude mouse model and in a murine bone marrow transplant model of FLT3-ITD-induced disease.
- Weisberg, E., Boulton, C., Kelly, L. M., Manley, P., Fabbro, D., Meyer, T., Gilliland, D. G., & Griffin, J. D. (2002). Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412. Cancer cell, 1(5), 433-43.More infoConstitutively activating FLT3 receptor mutations have been found in 35% of patients with acute myeloblastic leukemia (AML). Here we report the identification of a small molecule FLT3 tyrosine kinase inhibitor PKC412, which selectively induced G1 arrest and apoptosis of Ba/F3 cell lines expressing mutant FLT3 (IC(50) < 10 nM) by directly inhibiting the tyrosine kinase. Ba/F3-FLT3 cell lines made resistant to PKC412 demonstrated overexpression of mutant FLT3, confirming that FLT3 is the target of this drug. Finally, progressive leukemia was prevented in PKC412-treated Balb/c mice transplanted with marrow transduced with a FLT3-ITD-expressing retrovirus. PKC412 is a potent inhibitor of mutant FLT3 and is a candidate for testing as an antileukemia agent in AML patients with mutant FLT3 receptors.
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- Boulton, C. (2022). Southwest Regioanl Trauma Conference - Orthopedic Emergencies. Southwest Regioanl Trauma Conference.