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.

INTRODUCTION: The 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Correction to: Cluster identification, selection, and description in Cluster randomized crossover trials: the PREP-IT trials.

An amendment to this paper has been published and can be accessed via the original article.

Cluster identification, selection, and description in cluster randomized crossover trials: the PREP-IT trials.

BACKGROUND: In 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. METHODS: The PREP-IT program comprises two ongoing pragmatic cluster randomized crossover trials (Aqueous-PREP and PREPARE) which compare the effect of iodophor versus chlorhexidine solutions on surgical site infection and unplanned fracture-related reoperations in patients undergoing operative fracture management. We describe the process we used to identify and select orthopedic practices (clusters) for the PREP-IT trials, along with their characteristics. RESULTS: We identified 58 potential orthopedic practices for inclusion in the PREP-IT trials. After screening each practice for eligibility, we selected 30 practices for participation and randomized each to a sequence of interventions (15 for Aqueous-PREP and 20 for PREPARE). The majority of orthopedic practices included in the Aqueous-PREP and PREPARE trials were situated in level I trauma centers (100% and 87%, respectively). Orthopedic practices in the Aqueous-PREP trial operatively treated a median of 149 open fracture patients per year, included a median of 11 orthopedic surgeons, and had access to a median of 5 infection preventionists. Orthopedic practices in the PREPARE trial treated a median of 142 open fracture and 1090 closed fracture patients per year, included a median of 7.5 orthopedic surgeons, and had access to a median of 6 infection preventionists. CONCLUSIONS: The PREP-IT trials provide an example of how to follow the reporting standards for cluster randomized crossover trials by providing a clear definition of the cluster unit, a thorough description of the cluster identification and selection process, and sufficient description of key cluster characteristics. TRIAL REGISTRATION: Both trials are registered at ClinicalTrials.gov (A-PREP: NCT03385304 December 28, 2017, and PREPARE: NCT03523962 May 14, 2018).

Imaging of Pelvic and Femoral Fixation Hardware: Normal Findings and Hardware Failure.

Good 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.

Are Geriatric Patients Who Sustain High-Energy Traumatic Injury Likely to Return to Functional Independence?

OBJECTIVES: To 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. DESIGN: Retrospective. SETTING: Urban Level I trauma center. PATIENTS: Study group of 216 patients with high-energy trauma and comparison group of 117 patients with low-energy trauma. INTERVENTION: Injury mechanism (high- vs. low-energy mechanism). MAIN OUTCOME MEASUREMENT: Patient-Reported Outcomes Measurement Information System Physical Function (PROMIS PF) patient-reported outcome measure, and change in living situation and mobility. RESULTS: Physical function outcomes and return to independence differed between patients with high-energy and low-energy injuries. High-energy geriatric trauma patients had significantly higher PROMIS PF scores compared with low-energy geriatric trauma patients (PROMIS PF score 42.2 ± 10.4 vs. 24.6 ± 10.4, P < 0.001). High-energy geriatric trauma patients were able to ambulate outdoors without an assistive device in 67% of cases and were living independently 74% of the time in comparison with 28% and 45% of low-energy geriatric trauma patients, respectively (P < 0.001, P < 0.001). Multivariate linear regression analysis demonstrated that low-energy mechanism injury was independently associated with a 13.2 point reduction in PROMIS PF score (P < 0.001). CONCLUSIONS: Geriatric patients greater than 1 year out from sustaining a high-energy traumatic injury seem to be functioning within the expected range for their age, whereas low-energy trauma patients seem to be functioning substantially worse than both age-adjusted norms and their high-energy cohorts. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Orthopaedic trauma patients and smoking: Knowledge deficits and interest in quitting.

BACKGROUND: Smoking 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. METHODS: Single-centre cross-sectional cohort survey study. Patients were approached consecutively for participation. Patients 18 years or older with a new fracture in our clinic for follow-up were eligible. Smokers and nonsmokers were included and surveyed regarding demographics. Smokers were asked questions about fractures and general knowledge questions regarding the effects of smoking on health. Smokers' interest in smoking cessation was assessed with direct questions, and transtheoretical model stage of change was queried before and after survey administration. RESULTS: One hundred twelve patients participated (44 smokers, 68 nonsmokers; 75 male patients, 37 female patients). Forty-eight percent of smokers stated that the fracture made them more likely to quit. Smokers answered more questions incorrectly than did nonsmokers (p=0.003). An increased percentage of smokers were in favourable stages of change compared with a population-based tobacco survey (68% versus 54%, p=0.008). Survey administration increased interest in quitting in 48%, and 11% modified their stage of change towards quitting. Smokers scoring higher on knowledge questions had more than 2-fold increased odds of being in a favourable stage of change (p=0.013; odds ratio, 2.13; 95% confidence interval, 1.744-3.855). CONCLUSIONS: Compared with nonsmokers, smokers less fully understand the negative effects of smoking on fracture care and general health. A large proportion of orthopaedic trauma patients who smoke are interested in smoking cessation and are possibly further along the pathway to change than expected. Brief education through a survey can increase interest in quitting. Formal education intervention may improve cessation rates and fracture outcomes.

Lower Extremity Fracture Reduction: Tips, Tricks, and Techniques So That You Leave the Operating Room Satisfied.

It 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.

Internal anterior fixators for pelvic ring injuries: Do monaxial pedicle screws provide more stiffness than polyaxial pedicle screws?

OBJECTIVES: Little 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. METHODS: Using a commercially available synthetic bone model, 15 unstable pelvic ring injuries were simulated by excising the pubic bone through the bilateral superior and inferior rami anteriorly and the sacrum through the bilateral sacral foramen posteriorly. Three test groups were established: (1) traditional supra-acetabular external fixation, (2) INFIX with polyaxial screws, (3) INFIX with monaxial screws. Load was applied, simulating lateral compression force. Outcome measure was construct stiffness. RESULTS: The traditional external fixator constructs had an average stiffness of 6.21 N/mm ± 0.40 standard deviation (SD). INFIX with monaxial screws was 23% stiffer than the traditional external fixator (mean stiffness, 7.66 N/mm ± 0.86 SD; p = .01). INFIX with polyaxial screws was 26% less stiff than INFIX with monaxial screws (mean stiffness, 5.69 N/mm ± 1.24 SD; p = .05). No significant difference was noted between polyaxial INFIX and external fixators (mean stiffness, 6.21 N/mm ± 0.40 SD; p=.65). CONCLUSIONS: The performance of INFIX depends on the type of screw used, with monaxial screws providing significantly more stiffness than polyaxial screws. Despite the mechanical advantage of being closer to the bone, polyaxial INFIX was not stiffer than traditional external fixation.

Special topic: Ipsilateral femoral neck and shaft fractures--does evidence give us the answer?

Ipsilateral 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.

Predictive factors of distal femoral fracture nonunion after lateral locked plating: a retrospective multicenter case-control study of 283 fractures.

INTRODUCTION: Reported 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. PATIENTS AND METHODS: A retrospective review of 283 distal femoral fractures in 278 consecutive patients treated with LLP at three Level1 academic trauma centers. Nonunion was liberally defined as need for secondary procedure to manage poor healing based on unrestricted surgeon criteria. Patient demographics (age, gender), comorbidities (obesity, smoking, diabetes, chronic steroid use, dialysis), injury characteristics (AO type, periprosthetic fracture, open fracture, infection), and management factors (institution, reason for intervention, time to intervention, plate length, screw density, and plate material) were obtained for all participants. Multivariable analysis was performed using logistic regression to control for confounding in order to identify independent risk factors for nonunion. RESULTS: 28 of the 283 fractures were treated for nonunion, 13 were referred to us from other institutions. Obesity (BMI>30), open fracture, occurrence of infection, and use of stainless steel plate were significant independent risk factors (P<0.01). A predictive algorithm demonstrates that when none of these variables are present (titanium instead of stainless steel) the risk of nonunion requiring intervention is 4%, but increases to 96% with all factors present. When a stainless plate is used, obesity alone carries a risk of 44% while infection alone a risk of 66%. While Chi-square testing suggested no institutional differences in nonunion rates, the time to intervention for nonunion varied inversely with nonunion rates between institutions, indicating varying trends in management approach. DISCUSSION: Obesity, open fracture, occurrence of infection, and the use of stainless steel are prognostic risk factors of nonunion in distal femoral fractures treated with LLP independent of differing trends in how surgeons intervene in the management of nonunion.

Do locking screws work in plates bent at holes?

OBJECTIVES: To assess whether plate bending at a hole significantly changes the biomechanical properties of a locked screw. METHODS: Coronal plane bends of 5-, 15-, or 45-degree angles were placed in 3.5-mm locking compression plates with the apex at a locking hole. An additional 45-degree angle test group was created in which a threaded screw head insert was placed before bending. Ten plates were tested in each group and compared with nonbent controls in a stepwise cyclic loading protocol. RESULTS: Statistically significant differences in protocol survival were shown between the control group and the 15-degree angle (P = 0.006) and 45-degree angle (P = 0.0007) groups. An apparent decrease in protocol survival in the 5-degree angle group did not reach statistical significance (P = 0.17). The average number of cycles survived was significantly different between the control group and the 15-degree angle (P = 0.027) and 45-degree angle (P = 0.0002) groups. The mean cycles to failure for the 5-degree angle group was 16% lower than for controls but did not reach statistical significance (P = 0.37). The test group bent to an angle of 45 degrees after placement of a threaded screw head insert showed no difference in protocol survival or in mean number of cycles survived compared with the regular 45-degree angle group. CONCLUSION: Bending of a 3.5-mm locking compression plate by more than 5 degrees at a locking hole results in a statistically significant decrease in survival of the corresponding locked screw. This effect cannot be prevented by the placement of a threaded screw head insert before bending.

Intramedullary cannulated headless screw fixation of a comminuted subcapital metacarpal fracture: case report.

This 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.

FLT3 internal tandem duplication mutations induce myeloproliferative or lymphoid disease in a transgenic mouse model.

Activating 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.

Prognostic, therapeutic, and mechanistic implications of a mouse model of leukemia evoked by Shp2 (PTPN11) mutations.

The 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.

A large-scale screen for mutagen-sensitive loci in Drosophila.

In 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 <3% of that observed in wild type and thus defines a function required for both DNA repair and meiotic recombination. At least one allele of each new gene identified in this study is available at the Bloomington Stock Center.

Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs.

Abnormal 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.

PKC412 overcomes resistance to imatinib in a murine model of FIP1L1-PDGFRα-induced myeloproliferative disease.

FIP1L1-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.

CT53518, a novel selective FLT3 antagonist for the treatment of acute myelogenous leukemia (AML).

Up 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.

Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412.

Constitutively 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.

PML/RARalpha and FLT3-ITD induce an APL-like disease in a mouse model.

Acute 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.