Citations

Abstract While standard chemotherapeutics can initially induce remission in patients with acute myelogenous leukemia (AML), patients often relapse in part due to the protective bone marrow microenvironment, which promotes the survival of AML cells. Using an in vitro cell culture model of the bone marrow, our lab recently showed that differentiating osteoblasts potently protect AML cells from apoptosis. In addition, we found that differentiating osteoblasts treated with histone deacetylase inhibitors (HDACi) fail to protect AML cells in this model. Since HDACi decreased the expression of genes required for osteoblast differentiation, we hypothesize that blocking specific stage(s) of osteoblast differentiation may make AML cells within the bone marrow more susceptible to chemotherapy. We are currently disrupting specific osteoblast differentiation stages via molecular or therapeutic drug manipulation and exploring the impact on AML cell survival both in cell culture models of the bone marrow microenvironment and in a mouse model of AML. The results of our studies will characterize novel bone marrow molecular and cellular interactions that promote the survival of AML cells. Targeting these interactions in combination therapies may more completely eradicate the AML cell reservoir and better prevent relapse. Citation Format: Rosalie Sterner, Kimberly Kremer, Amel Dudakovic, Scott Kaufmann, Jennifer Westendorf, Andre van Wijnen, Karen Hedin. Manipulating osteoblast differentiation in order to inhibit protection of AML cells within the bone marrow. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3292.

Abstract Calcium-modulating cyclophilin ligand (CAML) is an endoplasmic reticulum (ER) protein that functions in a complex to mediate tail-anchored (TA) protein insertion into the ER membrane. CAML has also been implicated as a regulator of endocytic trafficking, modulator of intracellular calcium signaling, and essential factor for the survival and proliferation of specialized immune cells. To investigate the role of CAML in cell biology and cancer, we generated Eμ-Myc transgenic mice that carry a conditional deletion allele of CAML. From these mice, we derived B cell lymphoma cell lines driven by c-Myc and induced deletion of the CAML gene by treatment with tamoxifen to activate Cre-ERT2 in vitro. Homozygous loss of CAML in multiple independent B cell lymphoma lines activated apoptosis, while heterozygous deletion led to reduced cell proliferation. Apoptosis was inhibited by caspase inhibitor Q-VD-OPh or Bcl-2/xL overexpression; however, blocking apoptosis did not restore cell division. Loss of CAML did not activate the unfolded protein response, but did induce c-Jun and JNK phosphorylation. Structure-function studies indicated that lymphoma cell viability did not depend on interaction of CAML with TRC40, another component of TA protein insertion machinery. Conversely, expression of a minimal region of CAML that interacts with the TA insertion co-factor WRB was sufficient to rescue growth of CAML-deleted cells. In summary, our study demonstrates an essential pro-survival role for CAML in c-Myc-driven lymphomas. Future investigations will focus on the underlying mechanism of apoptosis in this system to advance our understanding of the biological functions of CAML, and consider CAML-dependent survival as a potential novel target for anticancer therapy. Citation Format: Jennifer C. Shing, Lonn D. Lindquist, Richard J. Bram. c-Myc-driven lymphomas require calcium-modulating cyclophilin ligand (CAML) for survival and proliferation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4412.

Purpose: Essential thrombocythemia, polycythemia vera, and myelofibrosis are rare chronic hematological malignancies known as myeloproliferative neoplasms (MPNs) and are characterized by deregulated myeloid lineage cell production, splenomegaly, and heterogeneous symptom profiles. MPN patients suffer from a significant symptom burden (eg, fatigue, depressive symptoms, early satiety) and an impaired overall quality of life (QoL). Current treatments typically include pharmacological approaches, which may come with additional side effects and may be limited by treatment-associated toxicities (ie, cytopenias). Nonpharmacological approaches such as physical activity may be beneficial for reducing symptom burden and improving QoL. To date, no studies have examined physical activity as a nonpharmacological approach in MPN patients despite preliminary evidence supporting its benefit in other hematological cancers. The purpose of this article is to (1) review the literature related to physical activity and specific hematological cancer subtypes and to (2) make suggestions for future research involving physical activity in MPN patients as a symptom management strategy. Methods: A brief review of studies examining physical activity in leukemias, lymphomas, and myelomas (excluding stem-cell transplant patients) was conducted. Results: There is preliminary evidence to suggest that physical activity may be an effective approach to improve patient-reported outcomes (fatigue, depression, anxiety, sleep), physical fitness (cardiovascular fitness, balance, body composition), and overall QoL in other hematological cancers. Conclusions: Based on encouraging findings in other hematological cancers, future research should examine the feasibility and effectiveness of physical activity in MPN patients.

AimsBiphenotypic sinonasal sarcoma (SNS) is a locally aggressive tumour that occurs in the sinonasal region. PAX3–MAML3 has recently been identified as a recurrent fusion gene event in this entity; however, a subset of tumours harbour alternative PAX3 rearrangement without the involvement of MAML3. In this study we sought to characterize the molecular profile of a large series of cases, with a special emphasis on tumours with alternative fusions.Methods and resultsForty‐four examples of SNS were screened by fluorescence in‐situ hybridization and reverse transcription polymerase chain reaction to better characterize its molecular profile and identify potential novel fusion genes. Twenty‐four were positive for PAX3–MAML3 (55%), 15 showed rearrangements of PAX3 without MAML3 involvement (34%), one showed rearrangement of MAML3 without PAX3 involvement, and four were negative for the involvement of either gene (9%). Among 15 cases with PAX3 involvement only, three were found to harbour PAX3–FOXO1. Two of these cases arose in the nasal cavities of female patients (aged 31 and 47 years), and one showed bilateral involvement of the nasal cavities of a 35‐year‐old male. A fourth case involved the skull base of a 47‐year‐old male, and was positive for PAX3–NCOA1. Patients with fusion‐negative tumours were slightly older.ConclusionMore than half of the SNSs in this series were positive for PAX3–MAML3. However, a subset of tumours may harbour alternative PAX3 fusion genes or show no involvement of PAX3. Except for a possible weak association between age and molecular profile, the overall morphological and immunophenotypic features of all cases seem to be similar. Because of the rarity of these tumours, the impact of the molecular profile on the clinical course of these tumours remains to be determined.

Ciliated muconodular papillary tumors (CMPTs) are rare peripheral lung lesions, characterized by papillary architecture and ciliated columnar cells admixed with mucinous cells and basal cells. They often have prominent surrounding intra-alveolar mucin, which can lead to diagnostic confusion with mucinous adenocarcinoma. Recognition of the ciliated component is the key to diagnosis of CMPT. The literature contains few reported cases to date, all occurring in East-Asian patients. Although follow-up data are limited, CMPT seems to be an indolent tumor with very good prognosis, leading some to question whether it is a reactive or hamartomatous lesion. However, a very recent molecular study has identified BRAF (40%) and EGFR (30%) alterations in CMPT, supporting a truly neoplastic process. Here for the first time, we report 4 cases of morphologically typical CMPT in western patients, occurring in 1 man (60 y) and 3 women (71 to 83 y). Interestingly, 1 case occurred in background of pronounced small airway disease with necrotizing bronchiolitis and multiple carcinoid tumorlets. We further analyzed 1 tumor using a 50 gene next-generation sequencing oncology panel that identified 2 pathogenic mutations (BRAF V600E and AKT1 E17K). Our study is the first to describe that CMPT can occur in western (non-Asian) patients. Our data confirm BRAF V600E mutation as a probable driver in a subset of these tumors, along with AKT1 mutation, which further supports that CMPT are indolent pulmonary neoplasms.

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AbstractBackgroundAlthough many apheresis centers offer extracorporeal photopheresis (ECP), little is known about current treatment practices.MethodsAn electronic survey was distributed to assess ECP practice internationally.ResultsOf 251 responses, 137 met criteria for analysis. Most respondents were from North America (80%). Nurses perform ECP at most centers (84%) and the majority of centers treat adults only (52%). Most centers treat fewer than 50 patients/year (83%) and perform fewer than 300 procedures/year (70%). Closed system devices (XTS and/or Cellex) are used to perform ECP at most centers (96%). The most common indications for ECP are acute/chronic skin graft versus host disease (89%) and cutaneous T‐cell lymphoma (63%). The typical wait time for ECP treatment is less than 2 weeks (91%). Most centers do not routinely perform quality control assessment of the collected product (66%). There are device‐specific differences in treatment parameters. For example, XTS users more frequently have a minimum weight limit (P = 0.003) and use laboratory parameters to determine eligibility for treatment (P = 0.03). Regardless of device used, the majority of centers assess the clinical status of the patient before each procedure. Greater than 50% of respondents would defer treatment for hemodynamic instability due to active sepsis or heart failure, positive blood culture in the past 24 h or current fever.ConclusionThis survey based study describes current ECP practices. Further research to provide evidence for optimal standardization of patient qualifications, procedure parameters and product quality assessment is recommended.

BackgroundQuantifying craving longitudinally during the course of withdrawal, early abstinence, and relapse is essential for optimal management of alcohol use disorder (AUD). In an effort to identify biological correlates of craving, we used proton magnetic resonance spectroscopy (1H‐MRS) to investigate the correlation between craving and glutamate levels in the left dorsolateral prefrontal cortex (LDLPFC) of patients with AUD.MethodsParticipants underwent 1H‐MRS of the LDLPFC with 2‐dimensional J‐resolved (2DJ) averaged PRESS. MRS data were processed with LCModel and cerebrospinal fluid (CSF)‐corrected to generate metabolite concentrations. The Penn Alcohol Craving Scale (PACS) and the 30‐day time line follow‐back (TLFB 30) were used to quantify craving for alcohol and drinking patterns, respectively.ResultsThere was a statistically significant positive correlation between CSF‐corrected glutamate ([Glu]) levels and PACS scores (n = 14; p = 0.005). When PACS scores were dichotomized (< or ≥median = 16), [Glu] levels were significantly higher in the high‐ versus low‐craving group (p = 0.007). In addition, there was a significant negative correlation between CSF‐corrected N‐acetyl aspartic acid ([NAA]) levels and mean number of drinks per drinking day in the past month (n = 13; TLFB 30; p = 0.012). When mean TLFB 30 was dichotomized (< or ≥median = 7.86), [NAA] levels were significantly lower in subjects that consumed more alcoholic beverages. There was no significant correlation between [Glu] and [NAA] levels with other measures of drinking behavior and or depression symptom severity.ConclusionsWhile limited by small sample size, these data suggest that glutamate levels in LDLPFC are associated with alcohol craving intensity in patients with AUD. Further study with larger sample size is needed to replicate this finding and evaluate the merits of glutamate spectroscopy as a biological correlate of alcohol craving intensity and a guide to treatment interventions.

Abstract Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P &lt; 10−8 seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type–specific expression quantitative trait locus and enhancer–gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P &lt; 10−5 in the three-cancer meta-analysis. Significance: We demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers. Cancer Discov; 6(9); 1052–67. ©2016 AACR. This article is highlighted in the In This Issue feature, p. 932

Background Intracranial aneurysms ( IAs ), abdominal aortic aneurysms ( AAAs ), and thoracic aortic aneurysms ( TAAs ) all have a familial predisposition. Given that aneurysm types are known to co‐occur, we hypothesized that there may be shared genetic risk factors for IAs , AAAs, and TAAs . Methods and Results We performed a mega‐analysis of 1000 Genomes Project‐imputed genome‐wide association study ( GWAS ) data of 4 previously published aneurysm cohorts: 2 IA cohorts (in total 1516 cases, 4305 controls), 1 AAA cohort (818 cases, 3004 controls), and 1 TAA cohort (760 cases, 2212 controls), and observed associations of 4 known IA , AAA , and/or TAA risk loci (9p21, 18q11, 15q21, and 2q33) with consistent effect directions in all 4 cohorts. We calculated polygenic scores based on IA ‐, AAA ‐, and TAA ‐associated SNP s and tested these scores for association to case‐control status in the other aneurysm cohorts; this revealed no shared polygenic effects. Similarly, linkage disequilibrium–score regression analyses did not show significant correlations between any pair of aneurysm subtypes. Last, we evaluated the evidence for 14 previously published aneurysm risk single‐nucleotide polymorphisms through collaboration in extended aneurysm cohorts, with a total of 6548 cases and 16 843 controls ( IA ) and 4391 cases and 37 904 controls ( AAA ), and found nominally significant associations for IA risk locus 18q11 near RBBP 8 to AAA (odds ratio [ OR ]=1.11; P =4.1×10 −5 ) and for TAA risk locus 15q21 near FBN 1 to AAA ( OR =1.07; P =1.1×10 −3 ). Conclusions Although there was no evidence for polygenic overlap between IAs , AAAs , and TAAs , we found nominally significant effects of two established risk loci for IAs and TAAs in AAAs . These two loci will require further replication.