Impact of Socioeconomic Status on Pretreatment Weight Loss and Survival in Non-Small-Cell Lung Cancer.

PURPOSE: Socioeconomic status (SES) influences health care outcomes, but the influence of primary payer on cancer-associated wasting is unknown. We hypothesized that primary payer as an indicator of SES would influence pretreatment cancer-associated weight loss and treatment outcomes. MATERIALS AND METHODS: Retrospective review of medical records identified 1,366 patients with non-small-cell lung cancer (NSCLC) consecutively treated at a tertiary care health system between January 1, 2006 and December 31, 2013. Insurance status was obtained from an institutional tumor registry. Cancer-associated weight loss was based on the validated international consensus definition of cachexia. Multivariable regression analyses were used to identify prognostic factors of pretreatment cancer-associated weight loss and survival. RESULTS: The cohort included a representative group of patients with a median age at diagnosis of 64 years, 47% females, and 33% patients of nonwhite race. Pretreatment cancer-associated weight loss was present at the time of NSCLC diagnosis in 17%, 14%, 32%, and 38% of patients with stage I, II, III, and IV disease, respectively. Pretreatment cancer-associated weight loss was associated with increasing age at diagnosis, black race, single marital status, tobacco use, and disease stage. Compared with private insurance, Medicaid insurance (odds ratio, 2.17; 95% CI, 1.42 to 3.30) and lack of insurance (odds ratio, 2.32; 95% CI, 1.50 to 3.58) were associated with pretreatment cancer-associated weight loss. Among cachectic patients, comorbidity, histology, tumor grade, and disease stage were prognostic of survival on multivariable analysis; however, primary payer was not. CONCLUSION: Pretreatment cancer-associated weight loss is common in patients with NSCLC, and its presence is significantly associated with lower SES. However, among patients with pretreatment cancer-associated weight loss, SES was not predictive of survival. Early use of cancer cachexia-directed therapies may improve outcomes, and further study on the biologic mechanisms of cancer cachexia will provide novel therapeutic avenues.

Prevalence and Survival Impact of Pretreatment Cancer-Associated Weight Loss: A Tool for Guiding Early Palliative Care.

PURPOSE: Cancer-associated weight loss is associated with poor prognosis in advanced malignancy; however, its pretreatment prevalence and survival impact are inadequately described in large cohorts. Such data, stratified by tumor type and stage, may facilitate the optimal and timely allocation of complementary care, leading to improvements in patient survival and quality of life. METHODS: We performed a retrospective cohort study of 3,180 consecutively treated adult patients with lung or GI (including colorectal, liver, and pancreatic) cancer. Pretreatment cancer-associated weight loss was based on the international consensus definition of cachexia. Prevalence and survival impact of pretreatment cancer-associated weight loss were evaluated using the Kaplan-Meier method and compared using log-rank test. RESULTS: Cancer-associated weight loss was observed at the time of cancer diagnosis in 34.1% of patients. Pretreatment weight loss was documented in 17.6%, 25.8%, 36.6%, and 43.3% of stage I, II, III, and IV cancers, respectively. Wasting was common regardless of tumor type, with prevalence at diagnosis ranging from 27.3% in patients with colorectal cancer to 53.4% in patients with gastroesophageal cancer. Pretreatment weight loss was associated with reduced overall survival after adjusting for stage, size, grade, comorbidity, age, sex, and tobacco history (hazard ratio, 1.26; 95% CI, 1.13 to 1.39). CONCLUSION: Pretreatment cancer-associated weight loss is common, even in early-stage disease, and is independently associated with reduced survival. Minimal weight loss represents a clinically distinct entity with an associated overall survival intermediate to that of no weight loss and overt wasting. Early diagnosis and treatment of cancer-associated wasting offers a novel therapeutic avenue for reducing cancer mortality.

Clinical efficacy and safety of surface imaging guided radiosurgery (SIG-RS) in the treatment of benign skull base tumors.

Frameless, surface imaging guided radiosurgery (SIG-RS) is a novel platform for stereotactic radiosurgery (SRS) wherein patient positioning is monitored in real-time through infra-red camera tracking of facial topography. Here we describe our initial clinical experience with SIG-RS for the treatment of benign neoplasms of the skull base. We identified 48 patients with benign skull base tumors consecutively treated with SIG-RS at a single institution between 2009 and 2011. Patients were diagnosed with meningioma (n = 22), vestibular schwannoma (n = 20), or nonfunctional pituitary adenoma (n = 6). Local control and treatment-related toxicity were retrospectively assessed. Median follow-up was 65 months (range 61-72 months). Prescription doses were 12-13 Gy in a single fraction (n = 18), 8 Gy × 3 fractions (n = 6), and 5 Gy × 5 fractions (n = 24). Actuarial tumor control rate at 5 years was 98%. No grade ≥3 treatment-related toxicity was observed. Grade ≤2 toxicity was associated with symptomatic lesions (p = 0.049) and single fraction treatment (p = 0.005). SIG-RS for benign skull base tumors produces clinical outcomes comparable to conventional frame-based SRS techniques while enhancing patient comfort.

Single-Isocenter Frameless Volumetric Modulated Arc Radiosurgery for Multiple Intracranial Metastases.

BACKGROUND: Stereotactic radiosurgery (SRS) is a well-accepted treatment for patients with intracranial metastases, but outcomes with volumetric modulated arc radiosurgery (VMAR) are poorly described. OBJECTIVE: To report our initial clinical experience applying a novel single-isocenter technique to frameless VMAR for simultaneous treatment of multiple intracranial metastases. METHODS: We performed a retrospective analysis of 15 patients undergoing frameless VMAR for multiple intracranial metastases using a single, centrally located isocenter in the period 2009 and 2011. Of these, 3 patients were treated for progressive or recurrent intracranial disease. A total of 62 metastases (median, 3 per patient; range, 2-13) were treated to a median dose of 20 Gy (range, 15-30 Gy). Three patients were treated with fractionated SRS. Follow-up including clinical examination and magnetic resonance imaging (MRI) occurred every 3 months. RESULTS: The median follow-up for all patients was 7.1 months (range, 1.1-24.3), with 11 patients (73.3%) followed until death. For the remaining 4 patients alive at the time of analysis, the median follow-up was 19.6 months (range, 9.2-24.3). Local control at 6 and 12 months was 91.7% (95% confidence interval [CI], 84.6%-100.0%) and 81.5% (95% CI, 67.9%-100.0%), respectively. Regional failure was observed in 9 patients (60.0%), and 7 patients (46.7%) received salvage therapy. Overall survival at 6 months was 60.0% (95% CI, 40.3%-88.2%). Grade 3 or higher treatment-related toxicity was not observed. The median total treatment time was 7.2 minutes (range, 2.8-13.2 minutes). CONCLUSION: Single-isocenter, frameless VMAR for multiple intracranial metastases is a promising technique that may provide similar clinical outcomes compared with conventional radiosurgery.

Primary rhabdomyosarcoma of the pineal gland.

OBJECTIVES: To report a case of primary rhabdomyosarcoma (RMS) of the pineal gland in an adult, as well as review the literature on this rare entity. METHODS: The case is compared with previous reports of similar entities, with emphasis on this patient's characteristics and clinical presentation, investigations, and management. RESULTS: Diagnosis of primary RMS of the pineal gland was based on the presence of strap cells and multinucleated myotube-like structures, as well as tumor cell expression of skeletal muscle markers consistent with myogenic differentiation. Multimodality treatment was initiated based on pediatric protocols. Unfortunately, the disease progressed on treatment, and the patient survived only 5 months from diagnosis. CONCLUSIONS: Pineal RMS is a rare disease with poor prognosis. Optimal management is unknown but likely to involve aggressive multimodality therapy.

Frameless single-isocenter intensity modulated stereotactic radiosurgery for simultaneous treatment of multiple intracranial metastases.

PURPOSE: Stereotactic radiosurgery (SRS) is well accepted treatment for patients with intracranial metastases, but the role of frameless radiosurgery is not well defined. Here, we describe our clinical experience applying a novel single-isocenter technique to frameless intensity modulated stereotactic radiosurgery (IMRS) for simultaneous treatment of multiple intracranial metastases. METHODS AND MATERIALS: Between 2006 and 2012, 100 consecutive patients received frameless IMRS for multiple intracranial metastases using a single, centrally-located isocenter. Among these, 29 patients were treated for progressive or recurrent intracranial disease. A total of 465 metastases (median, 4 per patient, range, 2-18) were treated to a median dose of 20 Gy (range, 15-50 Gy). Follow-up including clinical examination and magnetic resonance imaging (MRI) occurred every 3 months. RESULTS: Median follow-up for all patients was 4.3 months (range, 0.2-58.3 months), with 83 patients (83.0%) followed until their death. For the remaining 17 patients alive at the time of analysis, median follow-up was 9.2 months (range, 2.2-58.3 months). Overall survival at 6 months was 49.5% [95% confidence interval (CI), 35.3-63.6%]. Local control at 6 and 12 months was 88.9% (95% CI, 79.1-98.6%) and 81.5% (95% CI, 65.2-97.7%), respectively. Regional failure was observed in 39 patients (39%), and 25 patients (25%) received salvage therapy. Grade 3 or greater treatment-related toxicity was observed in 4 patients (4%) and included intracranial hemorrhage, seizure, and radionecrosis. Median total treatment time was 17.2 minutes (range, 2.8-55.3 minutes). CONCLUSIONS: Single-isocenter IMRS for multiple intracranial metastases can produce clinical outcomes comparable to those of conventional radiosurgery techniques.

Stereotactic body radiation therapy in octogenarians with stage I lung cancer.

BACKGROUND: The purpose of this study was to describe our clinical experience using stereotactic body radiation therapy (SBRT) to treat medically inoperable stage I non-small-cell lung cancer (NSCLC) in very elderly patients. PATIENTS AND METHODS: Twenty-four consecutive octogenarians with stage I NSCLC were treated with SBRT between 2007 and 2011 at a single center. Median prescription dose was 48 Gy (range, 48-56). Follow-up clinical examination and computed tomography (CT) were performed every 2 to 3 months. RESULTS: Median age was 85 years (range, 80-89). Twenty-three (96%) patients had peripheral tumors, and median tumor size was 22 mm (range, 11-49). Tissue diagnosis was obtained in 16 (67%) patients. Median follow-up for all patients was 27.6 months (range, 4.3-61.2). The 24-month disease-free survival was 77% (95% confidence interval [CI], 61%-97%). The 24-month overall survival (OS) was 74% (95% CI, 57%-94%). No local failure (LF) was observed during the period of observation. Nodal failure (NF) and distant failure (DF) occurred in 2 and 4 patients, respectively. The cumulative incidence of competing mortality at 24 months was estimated at 13% (95% CI, 3%-30%). No difference in outcomes with or without tissue diagnosis was observed. No grade ≥ 3 early or late treatment-related toxicities were observed. CONCLUSION: Octogenarians tolerate SBRT well, which makes it an attractive treatment option.

Reporting of cause-specific treatment effects in cancer clinical trials with competing risks: a systematic review.

BACKGROUND: Separate analysis of cause-specific treatment effects is important for interpreting results of randomized trials. We sought to determine the extent to which cause-specific effects on primary events are reported in contemporary randomized controlled trials in oncology. METHODS: We screened 833 randomized trials published in eight leading medical journals between January 2006 and December 2009. We excluded prevention studies (n=52), secondary reports (n=100), and one retracted study. Analysis was further restricted to 116 trials in non-metastatic/recurrent cancer that used an event-free survival primary endpoint. For each study included in the analysis, we evaluated whether treatment effects on both cancer and non-cancer events comprising the primary endpoint were reported separately and whether statistical analysis was provided. RESULTS: Of the 116 randomized trials, 47 (40%; 95% confidence interval (CI), 32-50%) reported effects on both cancer and non-cancer events comprising the primary endpoint, with statistical analysis provided in 13 (11%; 95% CI, 7-19%). Twenty-six trials (22%; 95% CI, 15-31%) reported effects on cancer but not non-cancer events, with statistical analysis provided in 11 (9%; 95% CI, 5-17%). In 43 studies (37%; 95% CI, 28-47%), no effects on cancer-specific components of the primary endpoint were given. Of these, 33 studies (28%; 95% CI, 21-38%) did report effects on some cancer-specific event, while ten (9%; 95% CI, 4-16%) did not report effects of treatment on any cancer event. DISCUSSION: Many randomized trials in oncology do not report cause-specific effects on primary events. Increased specificity is needed in the design and reporting of cancer clinical trials.

EGFR-mediated carcinoma cell metastasis mediated by integrin αvß5 depends on activation of c-Src and cleavage of MUC1.

Receptor tyrosine kinases and integrins play an essential role in tumor cell invasion and metastasis. We previously showed that EGF and other growth factors induce human carcinoma cell invasion and metastasis mediated by integrin αvß5 that is prevented by Src blockade. MUC1, a transmembrane glycoprotein, is expressed in most epithelial tumors as a heterodimer consisting of an extracellular and a transmembrane subunit. The MUC1 cytoplasmic domain of the transmembrane subunit (MUC1.CD) translocates to the nucleus where it promotes the transcription of a metastatic gene signature associated with epithelial to mesenchymal transition. Here, we demonstrate a requirement for MUC1 in carcinoma cell metastasis dependent on EGFR and Src without affecting primary tumor growth. EGF stimulates Src-dependent MUC1 cleavage and nuclear localization leading to the expression of genes linked to metastasis. Moreover, expression of MUC1.CD results in its nuclear localization and is sufficient for transcription of the metastatic gene signature and tumor cell metastasis. These results demonstrate that EGFR and Src activity contribute to carcinoma cell invasion and metastasis mediated by integrin αvß5 in part by promoting proteolytic cleavage of MUC1 and highlight the ability of MUC1.CD to promote metastasis in a context-dependent manner. Our findings may have implications for the use and future design of targeted therapies in cancers known to express EGFR, Src, or MUC1.

Correlation between radiation dose to ¹8F-FDG-PET defined active bone marrow subregions and acute hematologic toxicity in cervical cancer patients treated with chemoradiotherapy.

PURPOSE: To test the hypothesis that radiation dose to (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG-PET)-defined active bone marrow (BM(ACT)) subregions is correlated with hematologic toxicity in cervical cancer patients treated with chemoradiotherapy. METHODS AND MATERIALS: The conditions of 26 women with cervical cancer who underwent (18)F-FDG-PET before treatment with concurrent cisplatin and intensity-modulated radiation therapy were analyzed. BM(ACT) was defined as the subregion of total bone marrow (BM(TOT)) with a standardized uptake value (SUV) equal to or above the mean for that individual. Inactive bone marrow (BM(INACT)) was defined as BM(TOT) - BM(ACT). Generalized linear modeling was used to test the correlation between BM(ACT) and BM(INACT) dose-volume metrics and hematologic nadirs, particularly white blood cell count (WBC) and absolute neutrophil count (ANC). RESULTS: Increased BM(ACT) mean dose was significantly associated with decreased log(WBC) nadir (ß = -0.04; 95% CI, -0.07 to -0.01; p = 0.009), decreased log(ANC) nadir (ß = -0.05; 95% CI, -0.08 to -0.02; p = 0.006), decreased hemoglobin nadir (ß = -0.16; 95% CI, -0.27 to -0.05; p = 0.010), and decreased platelet nadir (ß = -6.16; 95% CI, -9.37 to -2.96; p < 0.001). By contrast, there was no association between BM(INACT) mean dose and log(WBC) nadir (ß = -0.01; 95% CI, -0.06 to 0.05; p = 0.84), log(ANC) nadir (ß = -0.03; 95% CI, -0.10 to 0.04; p = 0.40), hemoglobin nadir (ß = -0.09; 95% CI, -0.31 to 0.14; p = 0.452), or platelet nadir (ß = -3.47; 95% CI, -10.44 to 3.50; p = 0.339). CONCLUSIONS: Irradiation of BM subregions with higher (18)F-FDG-PET activity was associated with hematologic toxicity, supporting the hypothesis that reducing dose to BM(ACT) subregions could mitigate hematologic toxicity. Future investigation should seek to confirm these findings and to identify optimal SUV thresholds to define BM(ACT).

RBBP9: a tumor-associated serine hydrolase activity required for pancreatic neoplasia.

Pancreatic cancer is one of the most lethal malignancies. To discover functionally relevant modulators of pancreatic neoplasia, we performed activity-based proteomic profiling on primary human ductal adenocarcinomas. Here, we identify retinoblastoma-binding protein 9 (RBBP9) as a tumor-associated serine hydrolase that displays elevated activity in pancreatic carcinomas. Whereas RBBP9 is expressed in normal and malignant tissues at similar levels, its elevated activity in tumor cells promotes anchorage-independent growth in vitro as well as pancreatic carcinogenesis in vivo. At the molecular level, RBBP9 activity overcomes TGF-beta-mediated antiproliferative signaling by reducing Smad2/3 phosphorylation, a previously unknown role for a serine hydrolase in cancer biology. Conversely, loss of endogenous RBBP9 or expression of mutationally inactive RBBP9 leads to elevated Smad2/3 phosphorylation, implicating this serine hydrolase as an essential suppressor of TGF-beta signaling. Finally, RBBP9-mediated suppression of TGF-beta signaling is required for E-cadherin expression as loss of the serine hydrolase activity leads to a reduction in E-cadherin levels and a concomitant decrease in the integrity of tumor cell-cell junctions. These data not only define a previously uncharacterized serine hydrolase activity associated with epithelial neoplasia, but also demonstrate the potential benefit of functional proteomics in the identification of new therapeutic targets.

An integrin alpha(v)beta(3)-c-Src oncogenic unit promotes anchorage-independence and tumor progression.

Integrins regulate adhesion-dependent growth, survival and invasion of tumor cells. In particular, expression of integrin alpha(v)beta(3) is associated with progression of a variety of human tumors. Here we reveal a previously undescribed adhesion-independent role for integrin alpha(v)beta(3) in pancreatic cancer and other carcinomas. Specifically, alpha(v)beta(3) expressed in carcinoma cells enhanced anchorage-independent tumor growth in vitro and increased lymph node metastases in vivo. These effects required recruitment of c-Src to the beta(3) integrin cytoplasmic tail, leading to c-Src activation, Crk-associated substrate (CAS) phosphorylation and tumor cell survival that, unexpectedly, was independent of cell adhesion or focal adhesion kinase (FAK) activation. Pharmacological blockade of c-Src kinase activity or decreased expression of endogenous alpha(v)beta(3) integrin or c-Src not only inhibited anchorage-independent growth but also suppressed metastasis in vivo, yet these manipulations did not affect tumor cell migration or invasion. These data define an unexpected role for an integrin as a mediator of anchorage independence, suggesting that an alpha(v)beta(3)-c-Src signaling module may account for the aggressive behavior of integrin alpha(v)beta(3)-expressing tumors in humans.

Cultural competency in medical education: demographic differences associated with medical student communication styles and clinical clerkship feedback.

PURPOSE: We tested the significance of associations among students' demographics, communication styles, and feedback received during clerkships. METHODS: US medical students who completed at least one required clinical clerkship were invited between April and July 2006 to complete an anonymous, online survey inquiring about demographics, communication styles (assertiveness and reticence), feedback (positive and negative), and clerkship grades. The effects of self-identified race/ethnicity, gender, and generation (immigrant, first- or second-generation American) and their 2-way interactions on assertiveness, reticence, total positive and total negative feedback comments were tested using factorial analysis of covariance, controlling for age, clerkship grades, and mother's and father's education; pairwise comparisons used simple contrasts. Two-sided P values < .05 were considered significant. RESULTS: Medical students from 105 schools responded (N = 2395: 55% women; 57% white). Men reported more assertiveness than women (P = .001). Reticence (P < .001) and total positive comments (P = .006) differed by race/ethnicity; in pairwise contrasts, black, East Asian, and Native American/ Alaskan students reported greater reticence than white students (P < .001), and white students reported receiving more positive comments than black, and South and East Asian students. Race/ethnicity-by-generation (P = .022) and gender-by-generation (P = .025) interaction effects were observed for total negative comments; white first-generation Americans reported receiving the fewest and male immigrants reported receiving the most negative comments. CONCLUSIONS: Demographic differences in students' communication styles and feedback they received highlight a need for cultural competency training to improve medical student-teacher interactions, analogous to training currently advocated to improve physician-patient interactions.

Specific cross-talk between epidermal growth factor receptor and integrin alphavbeta5 promotes carcinoma cell invasion and metastasis.

Tyrosine kinase receptors and integrins play essential roles in tumor cell invasion and metastasis. Previously, we showed that epidermal growth factor (EGF) stimulation of pancreatic carcinoma cells led to invasion and metastasis that was blocked by antagonists of integrin alpha(v)beta(5). Here, we show that EGF stimulates metastasis of carcinoma cells via a Src-dependent phosphorylation of p130 CAS leading to activation of Rap1, a small GTPase involved in integrin activation. Specifically, EGF receptor (EGFR)-induced Src activity leads to phosphorylation of a region within the CAS substrate domain, which is essential for Rap1 and alpha(v)beta(5) activation. This pathway induces alpha(v)beta(5)-mediated invasion and metastasis in vivo yet does not influence primary tumor growth or activation of other integrins on these cells. These findings show cross-talk between a tyrosine kinase receptor and an integrin involved in carcinoma cell invasion and metastasis and may explain in part how inhibitors of EGFR affect malignant disease.

"Making the grade:" noncognitive predictors of medical students' clinical clerkship grades.

OBJECTIVES: Because clinical clerkship grades are associated with resident selection and performance and are largely based on residents'/attendings' subjective ratings, it is important to identify variables associated with clinical clerkship grades. METHODS: U.S. medical students who completed > or =1 of the following required clinical clerkships--internal medicine, surgery, obstetrics/gynecology, pediatrics, neurology and psychiatry--were invited to participate in an anonymous online survey, which inquired about demographics, degree program, perceived quality of clerkship experiences, assertiveness, reticence and clerkship grades. RESULTS: A total of 2395 medical students (55% women; 57% whites) from 105 schools responded. Multivariable logistic regression models identified factors independently associated with receiving lower clerkship grades (high pass/pass or B/C) compared with the highest grade (honors or A). Students reporting higher quality of clerkship experiences were less likely to report lower grades in all clerkships. Older students more likely reported lower grades in internal medicine (P = 0.02) and neurology (P < 0.001). Underrepresented minorities more likely reported lower grades in all clerkships (P < 0.001); Asians more likely reported lower grades in obstetrics/gynecology (P = 0.007), pediatrics (P = 0.01) and neurology (P = 0.01). Men more likely reported lower grades in obstetrics/gynecology (P < 0.001) and psychiatry (P = 0.004). Students reporting greater reticence more likely reported lower grades in internal medicine (P = 0.02), pediatrics (P = 0.02) and psychiatry (P < 0.05). Students reporting greater assertiveness less likely reported lower grades in all clerkships (P < 0.03) except IM. CONCLUSIONS: The independent associations between lower clerkship grades and nonwhite race, male gender, older age, lower quality of clerkship experiences, and being less assertive and more reticent are concerning and merit further investigation.

Reduced PU.1 expression causes myeloid progenitor expansion and increased leukemia penetrance in mice expressing PML-RARalpha.

PU.1 is a member of the ETS family of transcription factors that is known to be important for hematopoietic development. Recently, haploinsufficiency for PU.1 has been shown to cause a shift in myelomonocytic progenitor fate toward the myeloid lineage. We have previously shown that transgenic mice expressing PML-RARalpha (PR) and RARalpha-PML frequently develop acute promyelocytic leukemia (APL) in association with a large (>20 Mb) interstitial deletion of chromosome 2 that includes PU.1. To directly assess the relevance of levels of expression of PU.1 for leukemia progression, we bred hCG-PR mice with PU.1+/- mice and assessed their phenotype. Young, nonleukemic hCG-PR x PU.1+/- mice developed splenomegaly because of the abnormal expansion of myeloid cells in their spleens. hCG-PR x PU.1+/- mice developed a typical APL syndrome after a long latent period, but the penetrance of disease was 84%, compared with 7% in hCG-PR x PU.1+/+ mice (P < 0.0001). The residual PU.1 allele in hCG-PR x PU.1+/- APL cells was expressed, and complete exonic resequencing revealed no detectable mutations in nine of nine samples. However, PR expression in U937 myelomonocytic cells and primary murine myeloid bone marrow cells caused a reduction in PU.1 mRNA levels. Therefore, the loss of one copy of PU.1 through a deletional mechanism, plus down-regulation of the residual allele caused by PR expression, may synergize to expand the pool of myeloid progenitors that are susceptible to transformation, increasing the penetrance of APL.

Expression profiling of murine acute promyelocytic leukemia cells reveals multiple model-dependent progression signatures.

Leukemia results from the expansion of self-renewing hematopoietic cells that are thought to contain mutations that contribute to disease initiation and progression. Studies of the gene expression profiles of human acute myeloid leukemia samples has allowed their classification based on the presence of translocations and French-American-British subtypes, but it is not yet clear whether their molecular signatures reflect the initiating mutations or mutations acquired during progression. To begin to address this question, we examined the expression profiles of normal murine promyelocyte-enriched samples, nontransformed murine promyelocytes expressing human promyelocytic leukemia-retinoic acid receptor alpha (PML-RARalpha) fusion gene, and primary acute promyelocytic leukemia cells. The expression profile of nontransformed cells expressing PML-RARalpha was remarkably similar to that of wild-type promyelocytes. In contrast, the expression profiles of fully transformed cells from three acute promyelocytic leukemia model systems were all different, suggesting that the expression signature of acute promyelocytic leukemia cells reflects the genetic changes that contributed to progression. To further evaluate these progression events, we compared two high-penetrance acute promyelocytic leukemia models that both commonly acquire an interstitial deletion of chromosome 2 during progression. The two models exhibited distinct gene expression profiles, suggesting that the dominant molecular signatures of murine acute promyelocytic leukemia can be influenced by several independent progression events.