High-throughput mutation analysis in acute myeloid leukemia (AML).

Abstract Abstract 4874 Introduction: Acute Myeloid Leukemia (AML) is the most common type of acute leukemia in adults. About 50% of patients with AML have normal karyotype, and are categorized as intermediate risk group. However, the clinical behavior and response to treatment in this group is heterogeneous. As a result, there is strong interest in characterizing molecular genetic features in the intermediate-risk AML patients that might rectify their stratification risk. In this group, FLT3-ITD (Internal Tandem Duplication) and FLT3-TKD (Tyrosine Kinase Domain) mutations are known to confer unfavorable risk whereas NPM1 and CEBPA mutations are known to be favorable risk markers. The purpose of this study is to analyze the combination of NPM1 and CEBPA mutations in presence or absence of FLT3 mutations on prognosis of AML patients referred to the State's largest tertiary care center over a period of 10 years for the treatment of leukemia. Patients and Method: We performed a retrospective chart review of all patients with AML evaluated at University of Oklahoma Health Sciences Center between January 2000 and December 2010. Patient's age, gender, race, laboratory and clinical data as well as bone marrow biopsy and aspirate findings were reported. PCR and Fragment Analysis were conducted on all available DNA preserved bone marrow materials to test the FLT3, NPM1 and CEBPA mutations. For statistical analysis, Kaplan-Meyer curve was used. Results: A total of 239 patients were evaluated. Male to female ratio was 2/1. Median age at diagnosis was 46y. 21 out of the 239 patients were less than 18 year old. DNA samples were present on 132 patients and mutation analysis for FLT3, CEBPA and NPM1 was performed. Correlation between mutations and AML prognosis was determined. 67/132 (50.8 %) patients were categorized into intermediate risk group (majority of patients had normal cytogenetics). 14/67 (20.9%) pts were FLT3+ (FLT3-ITD or FLT3-TKD mutation). 17/67 (23.9%) were NPM1+. 7/67 (10.4%) were CEBPA +. Kaplan-Meier curve was used to identify cumulative proportion surviving over time. FLT3 presence or absence itself was not identified to be statistically significant (p 0.416) in terms of overall survival. Interestingly, presence or absence of combined NPM1/CEBPA mutation in FLT3 negative patients, among intermediate risk group, was found to be statistically significant (p<0.05) in determining overall survival. In this subgroup, presence of NPM1/CEBPA combination (NPM1+/CEBPA+) was associated with poor prognosis (figure 2, lower curve), while absence of NPM1/CEBPA combination (NPM1-/CEBPA-) carries a better prognosis (figure 2, upper curve). Conclusion: Results of our study highlight the importance of performing combinations of mutation analysis in evaluation of overall prognosis in AML patients. FLT3-/NPM1+ profile in patients with normal cytogenetics is thought to confer a favorable prognosis. We demonstrated in this study that using combination mutation analysis in patients with FLT3- can change the risk stratification in patients with intermediate risk group and might affect therapeutic interventions in this patient population. Larger prospective studies are needed in the future for further validation of our findings. Disclosures: No relevant conflicts of interest to declare.

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High-Throughput Drug Screening Identifies Pyrimethamine As a Potent and Selective Inhibitor of Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v124.21.2304.2304 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2304-2304

Author(s):

Amit Sharma ◽

Nidhi Jyotsana ◽

Courteney K. Lai ◽

Anuhar Chaturvedi ◽

Kerstin Görlich ◽

...

Keyword(s):

Cell Proliferation ◽

Acute Myeloid Leukemia ◽

High Throughput ◽

Dihydrofolate Reductase ◽

Drug Screening ◽

Validation Studies ◽

Myeloid Leukemia ◽

Leukemic Cell ◽

High Throughput Drug Screening ◽

Acute Myeloid

Abstract Introduction: Hematopoietic stem/progenitor cell differentiation is blocked in acute myeloid leukemia (AML) resulting in cytopenias and high risk of death. Most patients with AML become resistant to treatment due to lack of effective cytotoxic and differentiation fostering compounds. High expression of MN1 confers poor prognosis to AML patients and induces resistance to cytarabine and all-trans-retinoic acid (ATRA) induced differentiation. We thus set out to identify compounds which could potentially overcome the differentiation block in AML. Methods: Based on the above concepts and in an effort to identify novel compounds which are potent inducers of differentiation and apoptosis in AML, high-throughput drug screening was employed in the MN1 leukemic model. A total of 3580 bioactive compounds were tested in duplicate at a concentration of 2.5 µM using alamar blue fluorescence as readout. As MN1 cells are resistant to ATRA (at 1µM and even 10µM ATRA), the drug screening was performed in the presence of a clinically relevant dose of ATRA (1 µM) to identify compounds that concurrently act with the cytotoxic and/or differentiating effects of ATRA. To determine whether a compound was effective as monotherapy or if it synergized with ATRA, we also performed a validation phase study in which the IC50 of each candidate compound was tested alone and in combination with ATRA. Fifty-four inhibitors were chosen from the primary screen for further validation based on presumed mechanism of action and novelty. The shortlisted compound pyrimethamine (PMT) was validated for its differentiation and apoptosis promoting effects in various murine and human AML models. Results: Our high-throughput drug screening identified 117 compounds, which reduced MN1 leukemic cell proliferation by more than 80% above the ATRA-treated control in both replicates (inhibitors), 8 borderline inhibitors (one replicate with more than 80% inhibition and one with 74 to 80% inhibition), and 35 outliers, which inhibited cell proliferation by 80% or more in only one replicate. The biologic processes most frequently targeted by the 117 inhibitors were DNA replication (n=26), microtubule assembly (n=12), NF-kB pathway (n=8), dihydrofolate reductase (DHFR, n=3) and heat shock protein 90 (HSP90). Dihydrofolate reductase inhibitors, pyrimethamine and amethopterin/methotrexate emerged as top hits from the screening and preliminary validation studies. Validation studies identified the antifolate pyrimethamine (PMT) that potently induced apoptosis and differentiation in several murine and human leukemic cell lines when administered as a single agent. The cytotoxic effects of pyrimethamine were reversed by addition of an excess of folic acid whereas induction of myeloid differentiation at higher concentrations of pyrimethamine was not mediated through DHFR inhibition. We further evaluated the effect of pyrimethamine in an in vivo xenograft mouse model by subcutaneously inducing tumors with HL60 and THP1 cell lines. Oral pyrimethamine treatment significantly reduced tumor volumes after 14, 19 and 24 days post-transplantation and at death compared to solvent treated mice (P<0.01). The effect of pyrimethamine was further assessed in primary human AML cells and normal CD34+ cells by CFC assays. Colony numbers from primary AML cells, but not normal CD34+ bone marrow cells, were significantly reduced by pyrimethamine as compared to solvent control. Thus, our study identifies pyrimethamine as a candidate drug that is a potent and specific inducer of apoptosis and differentiation with the property of specifically targeting leukemic cells. Conclusion: Our high-throughput drug screening identified pyrimethamine as a potent and specific antileukemic compound and reinforces targeting of folate metabolism as a treatment strategy in acute myeloid leukemia. Disclosures No relevant conflicts of interest to declare.

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Mutation Analysis in 276 Cases of Newly Diagnosed Acute Myeloid Leukemia By Next Generation Sequencing: Association with Established Prognostic Variables and MRC Risk Groups

Blood ◽

10.1182/blood.v126.23.1392.1392 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1392-1392

Author(s):

Parsa Hodjat ◽

Kankana Ghosh ◽

Priyanka Priyanka ◽

Beenu Thakral ◽

Keyur P. Patel ◽

...

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Next Generation Sequencing ◽

Mutation Analysis ◽

Myeloid Leukemia ◽

Risk Groups ◽

Newly Diagnosed ◽

Generation Sequencing ◽

Acute Myeloid ◽

Who 2008

Abstract INTRODUCTION Acute myeloid leukemia (AML) is known to have numerous genomic aberrations that predict response to treatment and overall survival. We aimed to assess various mutations in newly diagnosed AML cases by next generation sequencing (NGS) and their association with various well-established clinicopathologic parameters and Medical Research Council (MRC) risk groups. MATERIALS AND METHODS We performed molecular studies on DNA extracted from bone marrow aspirate specimens in 276 newly diagnosed treatment na•ve AML patients presenting at a single referral institution from 08/2013 to 03/2015 as part of routine clinical work up in a CLIA certified molecular diagnostics laboratory. Cases met criteria for AML per WHO 2008 criteria. The entire coding sequences of 28 genes (ABL1, ASXL1, BRAF, DNMT3A, EGFR, EZH2, FLT3, GATA1, GATA2, HRAS, IDH1, IDH2, IKZF2, JAK2, KIT, KRAS, MDM2, MLL, MPL, MYD88, NOTCH1, NPM1, NRAS, PTPN11, RUNX1, TET2, TP53, WT1) were sequenced using a NGS-based custom-designed assay using TruSeq chemistry on Illumina MiSeq platform. FLT3 internal tandem duplications (ITD) and codon 835/836 point mutation were detected by PCR followed by capillary electrophoresis. CEBPA mutation analysis was performed on 262 patients by PCR followed by Sanger sequencing. Cases were categorized as favorable, intermediate and adverse groups as per revised MRC cytogenetic risk group classification. RESULTS Median age was 67 years. Patients included 167 (60.5%) males and 109 (39.5%) females. 38 (14%) and 6 (2%) patients had prior diagnosis of myelodysplastic syndrome and myeloproliferative neoplasms respectively. Hematologic parameters are as follows [median (range)]: Hb 8.7 g/dL (2.8-13.9), platelets 50.5 K/μ L (1-1109), WBC 5.4 K/μ L (0.4-620.4), ANC 0.9 K/μ L (0-145.7), AMC 0.3 K/μ L (0-98.1). Bone marrow (BM) blast % [median (range)] was 45.5% (5-96). LDH was 733 IU/dL (225-13156). Of 275 patients with cytogenetic analysis performed, 98 (35.64%) had diploid karyotype, 75 (27.27%) had one, 38 (13.82%) had two, 8 (2.91%) had three, 56 (20.36%) had > three abnormalities, 75 (27.27%) had monosomies and 62 (22.55%) had trisomies. Of 34 cases classified as AML with recurrent cytogenetic abnormalities per WHO 2008, 10 (3.64%) had t(8;21), 13 (4.73%) had inv(16), 1 (0.36%) had t(15;17), 3 (1.09%) had inv (3), 4 (1.45%) had t(9;11)(p22;q23) and 3 (1.09%) had t(6;9)(p23;q34). MRC risk categorization of the cases was as follows: favorable 24 (8.72%), intermediate 161 (58.55%) and adverse 90 (32.73%). Mutations identified by NGS are as detailed in Table 1. Of 56 patients with FLT3 mutations detected by PCR, the breakdown is as follows: FLT3 ITD (39, 14.13%), FLT3 D835 (16, 5.80%), FLT3, ITD + D835 (1, 0.36%). Of 262 patients assessed, CEBPA mutation was detected in 26 (9.92%). Thirty one (11.23%) cases had no mutations detected in the genes analyzed by NGS or PCR, 93 (33.70%) had mutations in one, 80 (28.98%) in two, 42 (15.22%) in three and 30 (10.87%) in > three genes. We found positive associations between mutated genes and various parameters as detailed in Table 2. CONCLUSIONS: AML is a heterogeneous group of myeloid neoplasms at the genetic level. Multiple genetic mutations in a large subset of cases likely indicate clonal evolution. A subset of mutations has significant association with well-established clinico-pathologic parameters like WBC. With longer follow-up, we could use this data to refine prognostic models for AML. Table 1. Genes Number of Cases Percentage of Cases FLT3 61 22.10 NPM1 48 17.39 NRAS 48 17.39 DNMT3A 47 17.03 TP53 45 16.30 IDH2 40 14.49 IDH1 33 11.96 TET2 32 11.59 ASXL1 30 10.87 RUNX1 30 10.87 PTPN11 13 4.71 KRAS 11 3.99 KIT 8 2.90 WT1 8 2.90 GATA2 7 2.54 EZH2 6 2.17 JAK2 4 1.45 MPL 2 0.72 ABL1 1 0.36 EGFR 1 0.36 GATA1 1 0.36 IKZF2 1 0.36 MDM2 1 0.36 MLL 1 0.36 MYD88 1 0.36 NOTCH1 1 0.36 Table 1. Mutated genes p value Hb NRAS, NPM1 <0.05, <0.04 Platelets TP53, IDH2 <0.03, <0.02 WBC FLT3, NRAS, TP53 <0.05, <0.05, <0.05 AMC NRAS, NPM1, TP53 <0.001, <0.02, <0.02 ABC FLT3 NPM1 <0.049, <0.02 PB blast % FLT3, NPM1, TP53, CEBPA <0.000, <0.002, <0.005, <0.000 BM blast % FLT3, NRAS, NPM1, TP53, IDH1, CEBPA >0.000, <0.0000, <0.014, <0.004, <0.002, <0.012 AMC: absolute monocyte count, ABC: absolute basophil count, PB: peripheral blood, BM: bone marrow Disclosures No relevant conflicts of interest to declare.

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P-110 Evaluation of a high throughput mutation-screening strategy in myelodysplastic syndrome patients and acute myeloid leukemia using Halogenomics™ targeted-gene enrichment technology

Leukemia Research ◽

10.1016/s0145-2126(13)70158-9 ◽

2013 ◽

Vol 37 ◽

pp. S72-S73

Author(s):

M. Karimi ◽

M. Dimitriou ◽

C. Nilsson ◽

M. Jansson ◽

H. Matsson ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myelodysplastic Syndrome ◽

High Throughput ◽

Myeloid Leukemia ◽

Mutation Screening ◽

Screening Strategy ◽

Gene Enrichment ◽

Enrichment Technology ◽

Acute Myeloid

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Comprehensive Quantitative Proteomic Profiling of the Pharmacodynamic Changes Induced By MLN4924 in Acute Myeloid Leukemia Cells Reveals Rational Targets for Combination Therapy

Blood ◽

10.1182/blood.v126.23.1271.1271 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1271-1271

Author(s):

Valeria Visconte ◽

Steffan T. Nawrocki ◽

Kevin R. Kelly ◽

Yingchun Han ◽

Anthony Possemato ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Board Of Directors ◽

High Throughput ◽

Myeloid Leukemia ◽

Rna Helicase ◽

Tumor Type ◽

Advisory Committees ◽

Bet Inhibitors ◽

The Impact ◽

Acute Myeloid

Abstract NEDDylation controls the ubiquitination and proteasomal degradation of proteins that are critical for cell survival, oncogenic transformation, and therapeutic sensitivity. MLN4924 (4924, Pevonedistat) is a first-in-class inhibitor of NEDDylation that has been evaluated in multiple phase I trials. Despite its preliminary efficacy in patients with relapsed/refractory acute myeloid leukemia (AML) and higher-risk myelodysplastic syndromes (MDS), the specific pharmacodynamic (PD) effects that mediate the anti-leukemic activity of 4924 have not been completely defined. We conducted comprehensive proteome profiling of MV4-11 FLT3 ITD+ cells to determine the global impact of inhibiting NEDDylation with 4924 on the AML proteome. MV4-11 cells were treated with 4924 (1 μM) for 24 hours and processed for high-throughput proteome quantification. Using a 2-fold PD change cut-off, 47 of 3,812 unique detected proteins were significantly upregulated by 4924 treatment (P < 0.05). The effects of 4924 on the levels of selected proteins were confirmed by immunoblotting. 4924 triggered increased levels of many established NEDD8 substrates including CDT1, p27, KEAP1, NUSAP1, and MLX. Other notable factors elevated by 4924 treatment included RRM2, BRD2, NQO1, regulators of cellular redox status (GCLM, TXNRD1, HMOX1), the DNA helicase DNA2, and the DNA replication factor ESCO2. Reactome network analysis demonstrated that the significantly affected proteins primarily clustered in the cell cycle, mitosis, and stress response pathways. A comparison of our proteomic data with a comprehensive SILAC analysis performed in A375 melanoma cells similarly treated with MLN4924 revealed that 34% (16/47) of the pharmacodynamically increased proteins were identical between the two analyses. These findings suggest that the repertoire of proteins that are modulated by 4924 may be tumor-type dependent. Notably, several of the proteins modulated by 4924 in our study could represent biomarkers for patient stratification. For example, the chromodomain helicase DNA binding protein CHD3 (fold change: 2.23) was reported to be elevated in patients with MYST3-CREBBP AML or AML with a monocytic phenotype and high FLT3 expression that experienced short complete remissions following conventional therapy. It would be worthwhile to investigate whether patients with high basal CHD3 levels derive less benefit from treatment with 4924. We also detected drug-induced changes in 27 members of the RNA helicase family including DDX41, in which mutations were recently reported in AML and MDS. Out of these 27 helicases, DDX24 and DDX54 were most increased (1.74- and 1.51-fold, respectively). Although the impact of drug treatment on individual helicases fell below our set threshold of significance, the collective data suggest that 4924 may have a previously undefined class effect on RNA helicase function. Further investigation is required to assess whether NEDD8 plays a novel role in the regulation of RNA helicases and to determine how this may impact 4924 efficacy. Additionally, several of the targets that were elevated following treatment with 4924 are directly actionable with existing approved and investigational drugs. For example, a proof of concept FLT3-ITD+AML xenograft study confirmed that known effects of azacitidine (AZA) on RRM2 antagonized MLN4924-mediated upregulation of RRM2 and synergistically increased efficacy (P <0.01), implying a potential relationship between RRM2 expression and clinical response that could be explored in the ongoing trial of 4924 plus AZA in elderly patients with AML (NCT0181426). The ability of 4924 to increase BRD2 levels may also heighten the sensitivity of AML cells to BET inhibitors, which represents another clinical implication that could be seamlessly translated into the clinic and investigated in trials of existing BET inhibitor combinations. We are currently assessing this possibility in preclinical models of AML. In summary, our study demonstrates that high-throughput proteomic technology is a powerful tool with potential applications in patient refinement and the identification of rational actionable targets for precision combination therapeutic strategies. These findings support the implementation of high-throughput proteomics as a synergistic complement to genomics in novel anticancer drug development. Disclosures Sekeres: Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; TetraLogic: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees.

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HO-1 promotes resistance to an EZH2 inhibitor through the pRB-E2F pathway: correlation with the progression of myelodysplastic syndrome into acute myeloid leukemia

Journal of Translational Medicine ◽

10.1186/s12967-019-2115-9 ◽

2019 ◽

Vol 17 (1) ◽

Cited By ~ 1

Author(s):

Zhengchang He ◽

Siyu Zhang ◽

Dan Ma ◽

Qin Fang ◽

Liping Yang ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

High Risk ◽

Myelodysplastic Syndrome ◽

Tumor Cells ◽

High Throughput ◽

Myeloid Leukemia ◽

High Throughput Sequencing ◽

Ezh2 Expression ◽

Very High ◽

Acute Myeloid

Abstract Background Myelodysplastic syndrome (MDS) can progress to acute myeloid leukemia (AML), and conventional chemotherapy (decitabine) does not effectively inhibit tumor cells. Enhancer of zeste homologue 2 (EZH2) and Heme oxygenase-1 (HO-1) are two key factors in patients resistance and deterioration. Methods In total, 58 MDS patients were divided into four groups. We analyzed the difference in HO-1 and EZH2 expression among the groups by real-time PCR. After treatment with Hemin or Znpp IX, flow cytometry was used to detect apoptosis and assess the cell cycle distribution of tumor cells. Following injection of mice with very high-risk MDS cells, spleen and bone marrow samples were studied by immunohistochemistry (IHC) and hematoxylin and eosin (H&E) staining. MDS cells overexpressing EZH2 and HO-1 were analyzed by high-throughput sequencing. The effect of HO-1 on the pRB-E2F pathway was analyzed by Western blotting. The effects of decitabine on P15INK4B and TP53 in MDS cells after inhibiting HO-1 were detected by Western blotting. Results Real-time PCR results showed that EZH2 and HO-1 expression levels were higher in MDS patients than in normal donors. The levels of HO-1 and EZH2 were simultaneously increased in the high-risk and very high-risk groups. Linear correlation analysis and laser scanning confocal microscopy results indicated that EZH2 was related to HO-1. MDS cells that highly expressed EZH2 and HO-1 infiltrated the tissues of experimental mice. IHC results indicated that these phenomena were related to the pRB-E2F pathway. High-throughput sequencing indicated that the progression of MDS to AML was related to EZH2. Using the E2F inhibitor HLM006474 and the EZH2 inhibitor JQEZ5, we showed that HO-1 could regulate EZH2 expression. HO-1 could stimulate the transcription and activation of EZH2 through the pRB-E2F pathway in MDS patients during chemotherapy, which reduced TP53 and P15INK4B expression. Conclusions EZH2 was associated with HO-1 in high-risk and very high-risk MDS patients. HO-1 could influence MDS resistance and progression to AML.

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Mutation analysis in 35 cases of newly diagnosed therapy-related acute myeloid leukemia (AML) by next-generation sequencing (NGS): A clinico-pathologic correlation.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.15_suppl.e18525 ◽

2016 ◽

Vol 34 (15_suppl) ◽

pp. e18525-e18525

Author(s):

Parsa Hodjat ◽

Kankana Ghosh ◽

Priyanka Priyanka ◽

Beenu Thakral ◽

Keyur Patel ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Next Generation Sequencing ◽

Mutation Analysis ◽

Myeloid Leukemia ◽

Newly Diagnosed ◽

Next Generation ◽

Pathologic Correlation ◽

Next Generation Sequencing Ngs ◽

Generation Sequencing ◽

Acute Myeloid

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Clinical Implementation of a Novel High-Throughput Screen of Primary Leukemia Cells to Customize Therapy for Relapsed/Refractory Acute Myeloid Leukemia (AML).

Blood ◽

10.1182/blood.v114.22.2657.2657 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2657-2657

Author(s):

Kristen M O'Dwyer ◽

David Shum ◽

Mark Heaney ◽

Renier J. Brentjens ◽

Peter Maslak ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

High Throughput ◽

Myeloid Leukemia ◽

Chemotherapeutic Agents ◽

Leukemia Cells ◽

Screening Assay ◽

Treatment Regimens ◽

Refractory Acute Myeloid Leukemia ◽

Acute Myeloid

Abstract Abstract 2657 Poster Board II-633 For most patients with relapsed and refractory acute myeloid leukemia, therapeutic success is unpredictable with current cytotoxic chemotherapeutic regimens. Moreover, multiple courses of therapy have been shown to result in co-morbid conditions, which can often preclude the patient from being able to receive the potentially curative therapy of allogeneic bone marrow transplantation. With the aim of identifying a successful chemotherapy regimen for these patients, based on patient-specific myeloid blast cell chemo-sensitivities, we have developed a high-throughput screening assay that utilizes primary (patient-derived) leukemia cells and tested for chemo-sensitivity against a panel of established chemotherapeutic agents as well as novel agents. In our laboratory, we were able to identify in vitro resistance against the various drugs already clinically administered, including cytarabine, etoposide, and anthracyclines. Importantly, we were able to show in vitro sensitivity to chemotherapy agents that had not been previously administered. The index patient was a 32-year-old woman with primary refractory acute myeloid leukemia who had received six different therapeutic regimens prior to our testing, all of which demonstrated in vitro resistance using our assay. The blasts were sensitive, however, to 6-thioguanine with an inhibitory concentration (IC50) of 70 nM. Based on the in vitro data, the patient began a combination treatment regimen containing oral 6-thioguanine as her white blood cell (WBC) count had increased to greater then 50,000 cells/ml on her previous therapy. Following a maintenance regimen with these agents, her circulating blast count decreased to less then 10,000 cells/ml, and she had partial recovery of the neutrophil count, resulting in a decrease in the overall leukemia burden. This result was not seen with her previous treatment regimens. Importantly, the majority of this therapy was administered in the outpatient setting. Subsequently, we have collected specimens from more than ten patients with AML and used this screening assay to predict their response to various chemotherapeutics. In each case, we have accurately predicted the in vivo clinical response (both sensitivity and resistance) to different chemotherapeutic agents. This demonstrates that the technology currently being used to screen drug therapy for patients with relapsed and refractory AML is clinically useful and has a potential role in designing individualized drug treatment regimens. Disclosures: No relevant conflicts of interest to declare.

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