Day 3 :
- Track 2: Functional Genomics and Cytogenetic Biomarkers
Track 5: Biomarkers of Exposure Response and Susceptibility
Track 6: Biomarkers for Disorders
Track 8: Biomarkers in Nanoscience
Chair
Claude Prigent
Institute of Genetics and Development of Rennes, France
Co-Chair
Sergey Suchkov
I.M.Sechenov First Moscow State Medical University, Russia
Session Introduction
Jens Wiltfang
Georg August University Göttingen, Germany
Title: Predictive molecular diagnosis of Alzheimer’s dementia: Towards new clinical models for preventive treatment
Biography:
Jens Wiltfang is a graduate from the Faculty of Medicine of Hannover where he obtained a PhD in Psychiatry. He is the Director of the Department of Psychiatry and Psychotherapy at the University Medical Center Göttingen (UMG). He is a neurologist and psychiatrist with wide experience in the field of neurodegenerative diseases. His activity includes the clinical characterization of patients with dementia and research on the biomarker discovery and validation. In particular his main expertise is on the field of cerebrospinal fluid and blood biomarkers for early diagnosis of neurodegenerative diseases, with special interest on Alzheimer’s disease and Parkinson’s disease.
Abstract:
There is an unmet need for first preventive that is disease-modifying, treatments of Alzheimer´s dementia (AD). However, preventive treatment calls for predictive diagnosis since novel preventive treatment options can only be offered if patients are identified during preclinical stages of the incipient AD. Per definition, a preclinical stage cannot be detected by clinical tools and accordingly, patients at high risk for later AD have to be identified by biomarker guided predictive diagnostics. The presentation will demonstrate that patients with preclinical AD can meanwhile be identified within the clinically heterogenous cohort of Mild Cognitive Impairment (MCI) with positive and negative predictive values of at least 90% by a multiparameter biomarker approach relying on CSF dementia biomarkers, MRI volumetry and/or F18-Amyloid-PET. In view of a prevalence of approximately 20% of preclinical AD within the MCI risk cohort the latter predictive values are clinically significant. Moreover, it will be critically discussed in how far first blood-based assays may support the identification of preclinical AD. Finally, the presentation will exemplify that novel diagnostic targets may indicate promising novel therapeutic targets.
Biography:
Gbandjaba Nagba Yendoubé has completed his PhD in biochemistry from Hassan IIUniversity Casablanca Morocco in 2013. As a student, he develops a good collaboration with Sherbrooke University in Canada and the International Pasteur Institute of Morocco. In 2009, he won a grant from the IRSC to accomplish his thesis in the Sherbrooke Research Centre on Ageing. Dr. Gbandjaba also called the whistle blower focuses his research on the development of oxidative stress biomarkers involved in cardiovascular diseases related to successful ageing. Dr. Gbandjaba has more than 52 publications including original research articles in reputed journals, case study, short communications, symposia and review articles.
Abstract:
Aim: The aim of the study was to investigate the Paraoxonase 1 (PON1) phenotype distribution and to measure oxidative stress markers (Vitamin E/CT, MDA) in healthy, diabetic and hemodialysis patients. Patients and Method: Three hundred subjects (healthy, diabetic and chronic renal failure patients) aged between 40 and 80 years were recruited for the study (divided in three groups of 100 subjects each). Total MDA content in plasma was measured by HPLC with thiobarbituric acid (TBA) and with fluorescence detection. Vitamin E (α-tocopherol) as the principal plasma antioxidant was also measured by HPLC with electrochemical detection. Results: Vitamin E-Tot. Cholesterol ratio increases significantly with age in diabetic patients (r= 0.30; p <0.01). Vitamin E - Total Cholesterol ratio decreases significantly with age in hemodialysis patients (r= ― 0.17; p<0.05) and in healthy subjects (r=―0.15; p=0.44). Plasma MDA concentration increases with age in diabetic patients (r= 0.09; p=0.15). The distribution of PON 1 phenotype in healthy, diabetic and hemodialysis patients was as follows: AA 79.31%, 75.00% and 69.31%; AB 14.94%, 19.04% and 20.45%; BB 5.74%, 5.95% and 10.22%. Adjusted odds ratio comparing the AA variant with the BB variant were 1.97 [95 % confidence interval (CI): 0.63-6.21] in hemodialysis patients. In diabetic patients, the adjusted odds ratio comparing the AA variant with the AB variant of PON1 were 1.37 [95% CI: 0.62-3.04]. Conclusion: Our studies show that PON1 phenotype distribution and oxidative stress markers are associated with cardiovascular diseases risk in diabetic and hemodialysis patients.
Vasile Foris
Medical University of Graz, Austria
Title: A comprehensive approach for blood-derived biomarker assessment in pulmonary hypertension
Biography:
Vasile Foris obtained his MD from University of Medicine and Pharmacy “Iuliu Hatieganu” Cluj-Napoca, Romania. He has been employed as a Junior Scientist at the Ludwig Boltzmann Institute for Lung Vascular Research in Graz, Austria, where he also joined the PhD Program “Molecular Medicine” of the Medical University of Graz. His research interests focused mainly on circulating progenitor cells as well as on clinically relevant blood-derived biomarkers for pulmonary hypertension. He is elected as a Clinical Fellow at the Department of Internal Medicine, Division of Pulmonology at the Medical University of Graz.
Abstract:
Background: Apelin, TNF-like Weak Inducer of Apoptosis (TWEAK), and Growth Differentiation Factor-15 (GDF15) may be suitable for screening and prognostic evaluation in Pulmonary Hypertension (PH).
Patients & Methods: We performed a power analysis based on a pilot study in 10 IPAH patients, 10 CTEPH and 10 controls for apelin-12, -13, -17, -36, TWEAK and GDF-15, resulting in n=31 IPAH patients and 24 CTEPH patients needed for a prospective study assessing apelin-17 and GDF-15 as compared to matched controls to provide 80% power for detection of differences.
Results: Apelin-17 was increased in IPAH and in CTEPH as compared to control (p<0.0001 CTRL vs. IPAH, p<0.001 CTRL vs. CTEPH). In addition, GDF-15 was elevated both in IPAH and in CTEPH as compared to control (p<0.0001 CTRL vs. IPAH, p<0.001 CTRL vs. CTEPH). GDF-15 was correlated with NT-proBNP in both IPAH and CTEPH. Area under the ROC curve for apelin-17 and GDF-15 were similar with an AUC of 0.86 and 0.83 respectively. A cut-off value of 1480 pg/mL for apelin-17, detected IPAH with a sensitivity of 68% and a specificity of 93%. A cut-off value of 1270 pg/ml for apelin-17, detected CTEPH with a sensitivity of 71% and a specificity of 87%.
Conclusion: Among apelin isoforms, apelin-17 may be a promising biomarker for IPAH and CTEPH and performs similar to GDF-15. Both biomarkers may be relevant for both IPAH and CTEPH.
Rinu Sharma
Guru Gobind Singh Indraprastha University, India
Title: Diagnostic implications of altered miRNA profiles in esophageal cancer
Biography:
Rinu Sharma has obtained her Master's degree in Biotechnology and PhD in Biochemistry from All India Institute of Medical Sciences. She is a Faculty in School of Biotechnology, Guru Gobind Singh Indraprastha University, India. She has published more than 20 papers in reputed international journals; some of which are the first reports. Her current areas of interest are identification of non-invasive blood based biomarkers for early diagnosis of esophageal cancer and functional analysis of significantly altered genes using gene silencing and proteomic approaches.
Abstract:
The asymptomatic nature of esophageal cancer (EC) at early stages of the disease results in late clinical presentation leads to poor prognosis and limited success of therapeutic modalities. Despite advancement in diagnostic and therapeutic strategies, the five year survival rate of the disease still remains less than 20%. This is primarily due to lack of sensitive and specific markers for early diagnosis and monitoring response to therapy for this disease. Hence, there is a pressing need for establishment of novel non-invasive or minimally-invasive biomarkers for esophageal cancer. Growing evidence suggests importance of alteration in microRNA (miRNA) expression in development and progression of cancer. Moreover, presence of miRNAs in various body fluids such as serum, plasma, saliva and urine has opened a new era of disease research. Our group is interested in deciphering the clinical and functional significance of miRNAs in esophageal cancer. We have evaluated the expression of a panel of miRNAs in tissues as well as sera of esophageal cancer patients. The analysis revealed significant dysregulation of these miRNAs in EC tissues as compared to matched distant nonmalignant tissues. Receiver operated curves generated for these miRNAs showed that they possessed significant diagnostic potential individually and as a panel. Moreover, relative levels of circulating miRNAs in serum significantly distinguished EC patients from normal controls with a high sensitivity. The present paper will discuss the individual as well as collective diagnostic potential of these miRNAs and their targets in EC.
Nalinee Sripaung
Ministry of Public Health, Thailand
Title: The usage of biomarkers in terms of biological exposure indices for health surveillance in Thailand
Biography:
Nalinee Sripaung has completed her degrees of BSc and MSc from universities in Thailand (Mahidol University and Chulalongkorn University respectively). She has completed her PhD at the age of 34 years from Tokyo Medical and Dental University (TMDU), Japan. She has ever been the Editorial Board Member of the repute. She has published more than 10 papers in reputed journals and government reports. Presently, She is the Director of Rayong Occupational Health and Environmental Development Center. She is serving as an Department of Disease Control of Thailand Committee on Thai Biological Indices (Thai BEIs).
Abstract:
Presently, the health risk assessment becomes important for health active surveillance. The significant types of chemicals residual and or metabolites in biological samples are selected to be the biomarkers for exposure assessment and susceptibility. The results of analytical laboratory of biomarkers concentration in biological samples are compared with the health surveillance standard values. This method are used as safety measure of exposure assessment to chemicals hazard and cancer susceptibility in occupations and environmental community. Besides, the combined effects of food, drug and other chemicals of daily life intake accompanied with the mistaken method of collecting, transferring and preserving biolological samples act as the interference factors of laboratory analyticals results. The other important interferences are the risk behaviour and the individaul differences. Thus, Department of Disease Control of Thailand has set the pilot project focused on the concentration of biomarkers, laboratory analyticals method and interfering factors of 26 chemicals (8 heavy metals, 12 volatile organic compounds, 2 pesticides, 2 gases and 2 types of radiation) for formal workers in Thailand Kingdom. This pilot project is aimed to be the tool for setting the policy of standard measure by usage of biomarkers for exposure assessment in the program of health active surveillance. This project will be involved with active surveillance and diminishment of burden diseases caused by chemicals. This tool of safety measure should be applied to prevent and control of Chemicals Diseases in any other risk area.
Pina J Trivedi
The Gujarat Cancer & Research Institute, India
Title: Clinical significance of cytogenetic biomarkers in acute myeloid leukemia: An Indian experience
Biography:
Pina J Trivedi has completed her PhD in March 2012 from Gujarat University. She is working in Cytogenetic department of The Gujarat Cancer & Research Institute (GCRI), Ahmedabad, Gujarat; India from last 18 years. She is also one of the Faculties in a Master degree course (MSc) Cancer Biology run by GCRI. She received a Young Scientist Award for oral presentation in Indian Society of Human Genetics conference during 2005 in cytogenetics category. She has more than 41 publications in national and international journals. She has recently visited Bremerhaven, Germany during May 6th to 8th 2014 for workshop on “Zyto vision in situ hybridization”.
Abstract:
Acute myeloid leukemia (AML) is a heterogeneous group of disorder. Recurrent translocations t (15; 17), t (8; 21) and inv (16) have good prognosis and are recognized as a biomarker for prognostication in AML, whereas loss and gain of different chromosome segments play a vital role in leukemogenesis. The aim of the present study was to appraise the clinical significance of numerical and structural chromosomal abnormalities in AML patients. Bone marrow/peripheral blood lymphocytes of 321 AML patients were carried out by cytogenetics and FISH and Multicolour FISH as and when required. Out of 321 patients, trisomy 8 showed the highest prevalence (n=14) and found as sole, complex and secondary change. Along with most commonly observed recurrent chromosomal abnormalities, there were loss and gain of different chromosomes also observed. The loss of sex chromosome was observed in the highest frequency (n=20). Gain of whole chromosomes were; 8 (X23), 10 (X5), 19 (X7), 21 (X10), 22 (X6) and loss of X (X6), Y (X17). Frequent breakpoints in structural abnormalities were gain or loss of different chromosomes i.e., 1q (X8), 5q (X5), 8q (X4), 9q (X5), 11p (X5), 11q (X8), 17q (X9) and 22q (X 6). Study revealed that the gain of chromosomal material was observed much more often than loss. Loss of tumor-suppressor genes d might be involved in mechanism of leukemogenesis. Gain as numerical abnormalities may affect gene-dosage and may play a significant role in the pathogenesis of AML. Study highlights the clinical significance of cytogenetics as an independent prognostic biomarker in AML providing the allocation for a stratified treatment approach of the disease.
Laura Gillis
BioStat Solutions, Inc., USA
Title: A Statistical Consideration on the Evaluation of Biomarkers
Biography:
Laura Gillis, Ph.D. is Associate Director of Biostatistics, at BioStat Solutions, Inc. (BSSI). She has over 20 years of consulting experience including five years in genetic data analysis. Her work at BSSI has included both GWAS and candidate gene studies focusing on both single and multi-biomarker association testing, gene level association testing and development of biomarker subgroups (i.e., patient stratification) for improved response to treatment in practical applications. Her experience also includes the analysis of biomarker discovery data in both, the vaccine development and oncology diagnostic field using epidemiological and proteomic assay data. Dr. Gillis received her Ph.D. in Statistics from Virginia Tech.
Abstract:
As the use of multiple types of biomarkers in companion diagnostics continues to grow, evaluation and validation becomes more critical and often more complicated. While DNA biomarkers are stable over time, proteomic biomarkers can change over time depending on disease progression. Epidemiological variables, such as age, often provide additional predictive capability. Combining these biomarkers can lead to better diagnostics, but statistical analysis becomes more complex. This presentation will present techniques that have proven successful in the evaluation of diverse biomarkers for disease and drug response.
Samia Perwaiz Khan
Ziauddin University, Pakistan
Title: Carotid arteries plaques regression in heterozygous familial hypercholesterolemia patients on statin therapy
Biography:
Samia Perwaiz Khan obtained her Medical Degree (MBBS) from Dow Medical College, Karachi. Her MPhil and PhD degrees were granted by Ziauddin University, Karachi where she is currently working as Professor of Pharmacology and PhD Program Coordinator. She has written 12 research articles which have been published in national and international journals with high impact factors. She has attended and presented papers at several national and international conferences where one of her papers was declared as the best oral presentation. She has been a Reviewer for national and international journals. Furthermore, she has been a member of organizing teams for national conferences, symposia and academic work shops. She also has clinical experience and in the past has worked at Sindh Institute of Urology and Transplant (SIUT), Karachi, as a Medical Officer.
Abstract:
The aim of this study is to compare carotid intima-media thickness (CIMT) variation and plaque regression in hypercholesterolemia patients on statin therapy for two years. One hundred and twenty cases of hyperlipidemia having total cholesterol more than 250 mg/dL and LDL-C levels above 160 mg/dL were selected from National Institute of Cardiovascular Diseases and Dr. Ziauddin Hospital, Karachi by performing lipid profiles after overnight fasting. Familial hypercholesterolemia was also diagnosed from premature coronary diseases, xanthomas, arcus cornealis, and family history of premature coronary diseases and by LDL-R gene mutation. B-mode ultrasound was done to show thickness of carotid intima-media on Toshiba (M # SSA-580A/E2) with linear probe. Measurement of CIMT in patients of heterozygous familial hypercholesterolemia patients was done by B-mode ultrasound of carotid arteries. Multiple soft and hard plaques were seen in heterozygous familial hypercholesterolemia (HeFH) patients in B-mode ultrasound of carotid arteries. The mean CIMT reduction in both treatment groups was significant, 0.11 mm in rosuvastatin group and 0.08 mm in atorvastatin group, regression in CIMT over a duration of two years therapy (*p<0.02). The total cholesterol reduced was 46% and reduction of LDL-C by 48% in patients on rosuvastatin as compared to total cholesterol 36% and LDL-C 37% in patients on atorvastatin for duration of 24 months (**p<0.001). Measure plaque before and after 2 years statin therapy by B-mode ultrasonography done along with measurement of thickness of carotid intima-media on Toshiba (M# SSA-580A/E2) with linear probe.
- Young Researchers Forum
Chair
Jens Wiltfang
Georg August University Göttingen, Germany
Session Introduction
Landoni E
University of Milan, Italy
Title: A comprehensive pipeline for biomarker discovery using circulating miRNA microarray data
Biography:
Landoni E, third-year PhD student at the University of Milan, works as biostatistician at the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan. Her research project involves the application of machine learning methods for the analysis of high-dimensional ‘omics’ data. In particular, her research is focused on the discovery and development of cancer molecular biomarkers, focusing on the implementation of feature selection algorithms together with the use of original and simple graphical representations of the results. Another area of her interests is nonparametric statistics, applied in particular to the fields of molecular biology and personalized medicine.
Abstract:
Circulating miRNAs have the potential as cancer biomarkers but no consolidated guidelines are established for discovery analyses. Several issues (e.g. data normalization, expected miRNA up-regulation in one of classes, sample size limitation) can affect results making many approaches unsuitable. We developed a structured pipeline with innovative applications of existing bioinformatics methods including: 1) an assumption-independent normalization method based on miRNA ratios in data pre-processing; 2) the combination of the results of two statistical tests (t- and Anderson Darling) to detect miRNAs with significant fold change or general distributional differences in class comparison; 3) the application of a bootstrap selection procedure together with machine learning techniques to guarantee result generalizability and study the inter connections among the selected miRNAs in class prediction. We applied the pipeline to compare hemolized and non-hemolized plasma samples, identifying four miRNAs known to be hemolysis-related (miR-486-5p, miR-92a, miR-451, miR-16) together with a new one, miR-22.
Jing Zhang
Royal Military College of Canada, Canada
Title: Mammalian hair follicles: Insights into microRNAs as a Traumatic Brain Injury (TBI) biomarker
Biography:
Jing Zhang is a recent PhD graduate from Carleton University under Dr.Kenneth Storey’s supervision and joined Dr.Valerie Langlois’ group as a Postdoctoral fellow in the fall of 2013. His field is molecular physiology and previous work includes investigating molecular mechanisms behind survival adaptions under extreme environmental conditions in various stress tolerant animal models. Currently, he is focusing on exploring the potential of hair follicle as a diagnostic tool for military activity-related medical conditions including traumatic brain injury (TBI) and operational stress disorders using transcriptomic approaches.
Abstract:
With the wide adoption of explosive-dependent weaponry, blast-induced traumatic brain injury (TBI) has become a significant medical issue for military personnel. Recently, the implementation of microRNAs (miRNA) as a clinical biomarker has proposed for diseases including several types of cancer. The interaction between miRNAs and their corresponding mRNA targets usually leads to translational silencing or mRNA degradation. This work investigates the involvement of miRNAs in primary shockwave-induced TBI responses in rat whisker follicles. With an advanced blast simulator, we assess the molecular responses in the whisker follicles in the rat model that was expose under a series of single blast intensities (15, 20, 25 and 30 psi). Gene networks for miRNA-dependent gene expression were constructed using sub-network enrichment analysis (SNEA) with respect to shared and shockwave intensity-specific microarray transcription profiling. Based on the SNEA analysis, core miRNAs (miR-26a, -27b, -29a, -34a, -181c and -183), were measured using quantitative RT-PCR. All the miRNA levels tested decreased in abundance in the whisker follicles following shockwave exposures. The results suggest shared responses across multiple intensity exposures, example miR-183 in all intensities, whereas exposures at 15 and 20 psi triggered specific miRNA expressions, i.e., miR-29a and -34a respectively. Multiple pathways and biological processes (example DNA repair and mRNA processing), were enriched following a gene set enrichment analysis (GSEA). Our study provides the first evidence that miRNAs are responsive to shockwave exposures in mammalian hair follicles and these molecules may be useful biomarkers for primary blast-induced TBI.
Surasawadee Ausavarat
Mahidol University, Thailand
Title: Efficacy of TSHR mRNA as a tumor marker in the follow-up of differentiated thyroid cancer
Biography:
Surasawadee Ausavarat has completed her Ph.D in Human Molecular Genetics from Chulalongkorn University, Thailand. Her research interests are human disease gene identification and characterization. Currently, she is a lecturer of Nuclear Chemistry Laboratory, Division of Nuclear Medicine and her current research is directed toward determining a molecular marker for thyroid cancer. She has published more than 7 papers in international peer journals.
Abstract:
Objectives: Measurement of serum thyroglobulin (sTg) by immunoassay is used as a tumor marker for differentiated thyroid cancer (DTC); however, the possible interference of endogenous anti-thyroglobulin antibodies (TgAb) and low sensitivity during thyroid hormone suppression may limit its clinical usefulness. Therefore, many researchers have evaluated the efficacy of thyroid-transcripts by molecular assay instead. Here we investigated the efficacy of thyroid-stimulating hormone receptor (TSHR) mRNA during thyroid hormone suppression especially in TgAb-positive patients.
Methods: We studied 160 patients with differentiated thyroid cancer and 27 normal subjects without history of thyroid disease. All patients had undergone near-total thyroidectomy and radioactive iodine ablation. Of the 160 patients, 49 (30.6%) were classified as in-remission, 111 patients (69.4%) were disease-persistence, of which, 27 patients (24.3%) were TgAb-positive. Quantification of TSHR mRNA was performed using real-time PCR.
Results: Median TSHR mRNA level of in-remission group was significantly different from disease-persistence in TgAb-positive patients, particularly in distant metastasis patients. Analysis of TSHR mRNA at 2.00 pgEq/µg total RNA enabled us to discriminate between remission and disease-persistence at sensitivity of 88.9% and specificity of 42.9%. However, there is no correlation between level of TSHR mRNA and sTg or TSHR mRNA and TSH in all groups.
Conclusion: We demonstrated that TSHR mRNA has greater sensitivity in prediction of disease-persistence in TgAb-positive patients than sTg during thyroid hormone suppression. Further study should emphasize the cost-effectiveness of routine usage of the assay in clinical practice.
Biography:
Mahjoubeh Jalali Sefid Dashti has completed her PhD in the field of Bioinformatics at the South African National Bioinformatics Institute, University of Western Cape and is currently continuing with her Post-doctoral studies at the same Institute. Her research interest lies in biomarker discovery through the application of clinical next generation sequencing in identifying the genetic cause of multifactorial and rare disorders. She is involved in a number of groundbreaking research projects including distal muscular dystrophy, ALS-motor neuron disease, Myasthenia Gravis, post-traumatic stress disorder, maturity onset diabetes of the young and atypical breast cancer in Africans.
Abstract:
Distal muscular dystrophy (DD) is a group of genetic muscle-wasting disorders resulting in distal muscle weakness. Candidate gene and region approaches have identified several different causative mutations in a number of families with different recent ancestry. Here, we report on novel functional variants that are strong candidates as the genetic cause of a unique form of autosomal dominant DD in a South African family of admixed ancestry. We performed whole exome sequencing in five affected family members and two (one related and one unrelated) controls which identified ~80000 exonic and splicing variants in each targeted exome. As the disease displays an autosomal dominant pattern of inheritance in the family, we hypothesized that the causative mutation was likely to be a novel heterozygous variant. Therefore, in addition to identifying variants shared by the affected members yet absent in the controls, we also filtered out variants seen in the public SNP databases. This resulted in 124 variants that were further filtered based on their potential deleterious impact on the encoded protein or were at a conserved site to arrive at nine functional nsSNPs and four INDELs. As it did not link any of the mutations to known muscular dystrophy genes, our in-house BioOntological Relationship Graph (BORG) semantic database was used to assess their potential indirect links to the disease based on their documented roles in gene functions, pathways and clinical/knockout phenotypes relevant to DD. This variant prioritization strategy resulted in the identification of two novel mutations that are strong candidates for being the cause of the novel autosomal dominant form of DD.
Sewa Rijal
Monash University, Australia
Title: Inositol polyphosphate 4-phosphatase II (INPP4B) is associated with chemo-resistance and poor outcome in AML
Biography:
Sewa Rijal has completed her PhD from Monash University. She recently published her work in the prestigious journal, blood of identifying a novel prognostic biomarker protein known as INPP4B in acute myeloid leukemia. Her work was part of an inside blood commentary and also highlighted in the Australian media by ABC news as a major breakthrough. Her finding has important implications in defining prognosis and treatment options for AML patients. She is currently undertaking Post-doctoral studies to understand the mechanism of INPP4B-mediated chemo-resistance in AML so that novel therapeutics may be designed for patients who fail chemotherapy.
Abstract:
Acute Myeloid Leukemia (AML) is an aggressive blood cancer that is usually fatal within weeks without effective therapy. Current treatment with standard chemotherapy agents fail to elicit complete clinical responses in 20-30% of cases. An understanding of the mechanisms that mediate resistance to chemotherapy in AML may uncover new onco-proteins amenable to medicinal targeting. Activation of the phosphoinositide 3-kinase (PI3-K)/AKT pathway is prevalent in AML and linked to chemotherapy failure and poor outcomes. Homeostatic regulation of PI3K activity is orchestrated by a triad of lipid phosphatases, categorized functionally as 3-, 4-, or 5-phosphoinositide phosphatases. The biological relevance of most of these phosphoinositide phosphatases in acute myeloid leukemia (AML) remains poorly understood. Mass-spectrometry based gene expression profiling of 3-, 4- and 5-phosphatases in human AML revealed significant overexpression of INPP4B. Analysis of an expanded panel of 205 AML cases at diagnosis revealed INPP4B overexpression in association with reduced responses to chemotherapy, early relapse and poor overall survival independent of other risk factors. Ectopic overexpression of INPP4B conferred leukemic resistance to cytosine arabinoside (ara-C), daunorubicin and etoposide. Expression of a phosphatase inert variant (INPP4B C842A) failed to abrogate resistance of AML cells to chemotherapy in vitro or in vivo. In contrast, targeted suppression of endogenously overexpressed INPP4B by RNAi sensitized AML cell lines and primary AML to chemotherapy. These findings demonstrate a previously unsuspected and clinically relevant role for INPP4B gain-of-function as a mediator of chemo-resistance and poor survival outcome in AML independent of its phosphoinositide phosphatase function.