Ramiro Garzon

The Ohio State University, Columbus, Ohio, United States

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Publications (104)975.55 Total impact

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    ABSTRACT: Targeting aberrant tyrosine kinase activity may impact clinical outcome in acute myeloid leukemia (AML). We conducted a phase I study of the tyrosine kinase inhibitor midostaurin with bortezomib alone and in combination with chemotherapy in patients with AML. Patients on dose levels 1 and 2 (DL1 & 2) received midostaurin 50 mg bid and escalating doses of bortezomib (1 to 1.3 mg/m2). Patients on DL3 or higher received midostaurin and bortezomib following chemotherapy with mitoxantrone, etoposide, cytarabine (MEC). None of the patients enrolled to DL1 & 2 had dose-limiting toxicities (DLTs) or a clinical response. Among patients enrolled to DL3 or higher, DLTs were peripheral neuropathy, decrease in ejection fraction and diarrhea. A 56.5% CR rate and 82.5% overall response rate (CR + CR with incomplete neutrophil or platelet count recovery) were observed. The midostaurin/bortezomib/MEC combination is active in refractory/relapsed AML, but is associated with expected drug-related toxicities (NCT01174888).
    No preview · Article · Jan 2016 · Leukemia & lymphoma
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    Full-text · Article · Nov 2015
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    ABSTRACT: Changes in the enzymatic activity of protein arginine methyltransferase (PRMT) 5 have been associated with cancer; however, the protein's role in acute myeloid leukemia (AML) has not been fully evaluated. Here, we show that increased PRMT5 activity enhanced AML growth in vitro and in vivo while PRMT5 downregulation reduced it. In AML cells, PRMT5 interacted with Sp1 in a transcription repressor complex and silenced miR-29b preferentially via dimethylation of histone 4 arginine residue H4R3. As Sp1 is also a bona fide target of miR-29b, the miR silencing resulted in increased Sp1. This event in turn led to transcription activation of FLT3, a gene that encodes a receptor tyrosine kinase. Inhibition of PRMT5 via sh/siRNA or a first-in-class small molecule inhibitor (HLCL-61) resulted in significantly increased expression of miR-29b and consequent suppression of Sp1 and FLT3 in AML cells. As a result, significant antileukemic activity was achieved. Collectively, our data support a novel leukemogenic mechanism in AML where PRMT5 mediates both silencing and transcription of genes that participate in a 'yin-yang' functional network supporting leukemia growth. As FLT3 is often mutated in AML and pharmacologic inhibition of PRMT5 appears feasible, the PRMT5-miR29b-FLT3 network should be further explored as a novel therapeutic target for AML.Leukemia accepted article preview online, 05 November 2015. doi:10.1038/leu.2015.308.
    Full-text · Article · Nov 2015 · Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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    ABSTRACT: Statins possess potent immunomodulatory effects that may play a role in preventing acute GVHD (aGVHD) following allogeneic hematopoietic cell transplantation (allo-HCT). We performed a Phase II study of atorvastatin for aGVHD prophylaxis when given to allo-HCT recipients and their HLA-matched sibling donors. Atorvastatin (40mg/day) was administered to sibling donors, beginning 14 days before the anticipated start of stem cell collection. Allo-HCT recipients (n=40) received atorvastatin (40mg/day) in addition to standard aGVHD prophylaxis. The primary endpoint was cumulative incidence of grades 2-4 aGVHD at day 100. Atorvastatin was well tolerated and there were no attributable grade 3-4 toxicities in donors or their recipients. Day 100 and 180 cumulative incidences of grade 2-4 aGVHD were 30% (95% CI 17- 45%) and 40% (95% CI 25-55%), respectively. One-year cumulative incidence of chronic GVHD was 43% (95% CI 32- 69%). One year non-relapse mortality and relapse incidences were 5.5% (95% CI 0.9-16.5%) and 38% (95% CI 18- 47%), respectively. One-year progression-free survival and overall survival were 54% (95% CI 38-71%) and 82% (95% CI 69-94%). One-year GVHD-free, relapse-free survival (GRFS) was 27% (95% CI 16-47%). These results did not differ from our historical controls (N=96). While safe and tolerable, the addition of atorvastatin did not appear to provide any benefit to standard GVHD prophylaxis alone. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
    No preview · Article · Aug 2015 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
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    ABSTRACT: Current treatments for acute myeloid leukemia (AML) are designed to target rapidly dividing blast populations with limited success in eradicating the functionally distinct leukemia stem cell (LSC) population, which is postulated to be responsible for disease resistance and relapse. We have previously reported high miR-126 expression levels to be associated with a LSC-gene expression profile. Therefore, we hypothesized that miR-126 contributes to 'stemness' and is a viable target for eliminating the LSC in AML. Here we first validate the clinical relevance of miR-126 expression in AML by showing that higher expression of this microRNA (miR) is associated with worse outcome in a large cohort of older (>60 years) cytogenetically normal AML patients treated with conventional chemotherapy. We then show that miR-126 overexpression characterizes AML LSC-enriched cell subpopulations and contributes to LSC long-term maintenance and self-renewal. Finally, we demonstrate the feasibility of therapeutic targeting of miR-126 in LSCs with novel targeting nanoparticles (NP) containing antagomiR-126 resulting in in vivo reduction of LSCs likely by depletion of the quiescent cell subpopulation. Our findings suggest that by targeting a single miR, i.e., miR-126, it is possible to interfere with LSC activity, thereby opening potentially novel therapeutic approaches to treat AML patients.Leukemia accepted article preview online, 09 June 2015. doi:10.1038/leu.2015.139.
    No preview · Article · Jun 2015 · Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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    ABSTRACT: High levels of miR-155 are associated with poor outcome in acute myeloid leukemia (AML). In AML, miR-155 is regulated by NF-κB, the activity of which is in part controlled by NEDD8-dependent ubiquitin ligases. We demonstrate that MLN4924, an inhibitor of NEDD8 activating enzyme (NAE) presently being evaluated in clinical trials, decreases binding of NF-κB to the miR-155 promoter and downregulates miR-155 in AML cells. This results in upregulation of the miR-155 targets SHIP1, an inhibitor of the PI3K/Akt pathway, and PU.1, a transcription factor important for myeloid differentiation, leading to monocytic differentiation and apoptosis. Consistent with these results, overexpression of miR-155 diminishes MLN4924-induced antileukemic effects. In vivo, MLN4924 reduces miR-155 expression and prolongs survival of mice engrafted with leukemic cells. Our study demonstrates the potential of miR-155 as a novel therapeutic target in AML via pharmacologic interference with NF-κB-dependent regulatory mechanisms. We show the targeting of this oncogenic microRNA with MLN4924, a compound presently being evaluated in clinical trials in AML. Since high miR-155 levels have been consistently associated with aggressive clinical phenotypes, our work opens new avenues for microRNA-targeting therapeutic approaches to leukemia and cancer patients.Leukemia accepted article preview online, 14 May 2015. doi:10.1038/leu.2015.106.
    No preview · Article · May 2015 · Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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    ABSTRACT: The prognosis of AML is poor, highlighting the need for novel treatments. Hypomethylating agents, including decitabine are used to treat elderly AML patients with relative success. Targeting nuclear exporter receptors (Exportin 1, XPO1) is a novel approach to restore tumor suppressor (TS) function in AML. Here, we show that sequential treatment of AML blasts with decitabine followed by selinexor (XPO1 inhibitor) enhances antileukemic effects of selinexor. These effects could be mediated by the re-expression of a subset of TS (CDKN1A and FOXO3A) that are epigenetically silenced via DNA methylation, and cytoplasmic-nuclear trafficking is regulated by XPO1. We observed a significant upregulation of CDKN1A and FOXO3A in decitabine versus control treated cells. Sequential treatment of decitabine followed by selinexor in MV4-11 xenograft model significantly improved survival compared to selinexor alone. Based on these preclinical results, a Phase 1 clinical trial of decitabine followed by selinexor in elderly AML has been initiated. Copyright © 2015 American Society of Hematology.
    Full-text · Article · Feb 2015 · Blood
  • Parvathi Ranganathan · Ramiro Garzon
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    ABSTRACT: It is now established that deregulated microRNA (miRNA) expression is a prominent feature in acute myeloid leukemia (AML). Subsequently, functional studies have shown that miRNAs play an important role in the pathogenesis of AML by acting as tumor suppressors or oncogenes. Recent data indicate that distinctivemi RNA expression signatures are associated with chemotherapy response and clinical outcome and that targeting miRNAs in AML is a novel emerging therapeutic strategy. In this chapter, we will discuss the clinical application of miRNAs as biomarkers for diagnosis and prognosis in AML and review the current strategies to target miRNAs in this disease.
    No preview · Article · Jan 2015
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    ABSTRACT: Long noncoding RNAs (lncRNAs) are transcripts longer than 200 nucleotides, located within the intergenic stretches or overlapping antisense transcripts of protein coding genes. LncRNAs are involved in numerous biological roles including imprinting, epigenetic regulation, apoptosis, and cell cycle. To determine whether lncRNAs are associated with clinical features and recurrent mutations in older patients (aged ≥60 y) with cytogenetically normal (CN) acute myeloid leukemia (AML), we evaluated lncRNA expression in 148 untreated older CN-AML cases using a custom microarray platform. An independent set of 71 untreated older patients with CN-AML was used to validate the outcome scores using RNA sequencing. Distinctive lncRNA profiles were found associated with selected mutations, such as internal tandem duplications in the FLT3 gene (FLT3-ITD) and mutations in the NPM1, CEBPA, IDH2, ASXL1, and RUNX1 genes. Using the lncRNAs most associated with event-free survival in a training cohort of 148 older patients with CN-AML, we derived a lncRNA score composed of 48 lncRNAs. Patients with an unfavorable compared with favorable lncRNA score had a lower complete response (CR) rate [P < 0.001, odds ratio = 0.14, 54% vs. 89%], shorter disease-free survival (DFS) [P < 0.001, hazard ratio (HR) = 2.88] and overall survival (OS) (P < 0.001, HR = 2.95). The validation set analyses confirmed these results (CR, P = 0.03; DFS, P = 0.009; OS, P = 0.009). Multivariable analyses for CR, DFS, and OS identified the lncRNA score as an independent marker for outcome. In conclusion, lncRNA expression in AML is closely associated with recurrent mutations. A small subset of lncRNAs is correlated strongly with treatment response and survival.
    Full-text · Article · Dec 2014 · Proceedings of the National Academy of Sciences
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    ABSTRACT: There are 481 ultra-conserved regions (UCRs) longer than 200 bases in the genomes of human, mouse and rat. These DNA sequences are absolutely conserved and show 100% identity with no insertions or deletions. About half of these UCRs are reported as transcribed and many correspond to long non-coding RNAs (lncRNAs). We used custom microarrays with 962 probes representing sense and antisense sequences for the 481 UCRs to examine their expression across 374 normal samples from 46 different tissues and 510 samples representing 10 different types of cancer. The expression in embryonic stem cells of selected UCRs was validated by real time PCR. We identified tissue selective UCRs and studied UCRs in embryonic and induced pluripotent stem cells. Among the normal tissues, the uc.283 lncRNA was highly specific for pluripotent stem cells. Intriguingly, the uc.283-plus lncRNA was highly expressed in some solid cancers, particularly in one of the most untreatable types, glioma. Our results suggest that uc.283-plus lncRNA might have a role in pluripotency of stem cells and in the biology of glioma.
    Full-text · Article · Sep 2014 · Genome Medicine
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    ABSTRACT: Background: The purpose of this study is to determine whether microRNA for pluripotent stem cells are also expressed in breast cancer and are associated with metastasis and outcome. Methods: We studied global microRNA profiles during differentiation of human embryonic stem cells (n =26) and in breast cancer patients (n = 33) and human cell lines (n = 35). Using in situ hybridization, we then investigated MIR302 expression in 318 untreated breast cancer patients (test cohort, n = 22 and validation cohort, n = 296). In parallel, using next-generation sequencing data from breast cancer patients (n = 684), we assessed microRNA association with stem cell markers. All statistical tests were two-sided. Results: In healthy tissues, the MIR302 (high)/MIR203 (low) asymmetry was exclusive for pluripotent stem cells. MIR302 was expressed in a small population of cancer cells within invasive ductal carcinoma, but not in normal breast (P < .001). Furthermore, MIR302 was expressed in the tumor cells together with stem cell markers, such as CD44 and BMI1. Conversely, MIR203 expression in 684 breast tumors negatively correlated with CD44 (Spearman correlation, Rho = -0.08, P = .04) and BMI1 (Rho = -0.11, P = .004), but positively correlated with differentiation marker CD24 (Rho = 0.15, P < .001). Primary tumors with lymph node metastasis had cancer cells showing scattered expression of MIR302 and widespread repression of MIR203. Finally, overall survival was statistically significantly shorter in patients with MIR302-positive cancer cells (P = .03). Conclusions: In healthy tissues the MIR302(high)/MIR203(low) asymmetry was characteristic of embryonic and induced pluripotency. In invasive ductal carcinoma, the MIR302/MIR203 asymmetry was associated with stem cell markers, metastasis, and shorter survival.
    No preview · Article · Sep 2014 · JNCI Journal of the National Cancer Institute
  • Ramiro Garzon · Parvathi Ranganathan
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    ABSTRACT: Long noncoding RNAs (lncRNAs), products of pervasive transcription of the human genome, have emerged as important epigenetic regulators of cancer development and progression. LncRNAs, with transcript size ranging from 200 bp to 100 Kb, perform a diverse array of biological roles including chromatin modification, pre- and post-transcriptional regulation, control of cell division, cell-cycle growth and proliferation and imprinting. They exhibit cell-specific expression patterns as well as restricted subcellular distribution, and have shown to play a role in multiple cancers such as cancers of the breast, pancreas, liver, lung and colon. Owing to the role they play in cancer initiation and progression, they have emerged as a new class of prognostic indicators, markers of chemotherapy response and finally show promise as targeted therapy against cancer. This article explores the characteristics of lncRNAs, function and association with multiple cancers and highlights the recent progress made on these new molecules especially with respect to cancer. Key Concepts: Long noncoding RNAs are a new class of epigenetic regulatory molecules that are actively transcribed from the human genome. Involved in multiple biological functions including imprinting, transcriptional and post-transcriptional regulation of gene expression, cell growth, proliferation and differentiation. Dysregulation of lncRNA observed in multiple cancer types, involved in cancer progression and metastasis. LncRNAs can serve as biomarkers, prognostic indicators and predictors of chemotherapy response. Attractive targets for a new group of targeted therapy. Keywords:long noncoding RNAs;epigenetic regulation;chromatin remodelling;cancer initiation and progression;biomarkers;targeted therapy
    No preview · Chapter · Jun 2014
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    ABSTRACT: Background: aGVHD is one of the most frequent and lethal complications after allo HSCT, underscoring the need to develop novel therapies. To achieve this goal, aGVHD mechanisms needs to be further elucidated. Recently it was reported that miRNAs modulate aGVHD. We hypothesize that serum miRNAs expression is deregulated in aGVHD and could play a role in aGVHD pathogenesis. Aims: To asses serum miRNAs expression in aGVHD and dissect their functional role. Methods: We performed serum miRNA expression analysis using deep-sequencing (Solid Platform) from allo HSCT recipients samples. Peripheral blood samples were collected weekly until day 100+ and at the time of clinical diagnosis of aGVHD. A mouse model of aGVHD (B6 donor into F1 recipients) was used to assess serum miRNA expression in animals with aGVHD. Functional studies were performed using miR-29a and miR-16 Dotap formulations using mouse dendritic and T cells. Cytokines were measured using ELISA. Results: We included 10 patients with aGVHD (bowel n=2; skin (n=5) and both skin/bowel (n=3)). Conditioning regimens were mainly non-myeloablative (n=9) using unrelated donors (n=9). Allo HSCT patients with no aGVHD, matched for age, disease, conditioning regimen, donor and timing of sample collection were used as controls. We compared miRNA expression between all patients with aGVHD (n=10) and controls (n=7) using class comparison. Among the 7 miRNAs up-regulated in aGVHD samples we found miR-29a (Fold change (FC) >2, p<0.01). Since miR-29a is involved in immune regulation we validated this miR by RT-PCR in the B6-F1 model of murine aGVHD (miR-29a levels were 4.9 higher in aGVHD mice (n=6) than controls (n=4) p<0.01). Since our group reported before that miR-29a binds as ligands to TLR7/8, we hypothesized that serum miR-29a could bind to TLR7/8 of APCs activating NFkB and enhancing alloreactive responses during aGVHD. First, we examined whether extracellular miR-29a could activate dendritic cells (DCs). B6D2F1 splenocytes were stimulated with Dotap formulations (mimicking exosomes) of miR-29a. We found that CD69 expression measured by FACS is significantly elevated in CD11c+ DCs/CD4+ and CD8+ T cells treated with miR-29a compared to controls (Dotap alone or Dotap-miR16). To investigate whether T cells could be activated by the miR alone, untouched resting T cells from mouse spleen were isolated and stimulated with Dotap-miR-29a or controls. CD69 was not upregulated indicating that the activation of T cells was dependent on APC activation. To further confirm that miR-29a could activate DCs, we isolated murine DCs and repeated the above experiment. We found that miR-29a stimulation of DCs but not controls induced the up-regulation of canonical DC maturation and activation markers, CD40, CD80 and CD86. Furthermore, miR-29a Dotap treatment of DCs alone stimulated the release of TNFα (114.2±14 pg/ml vs. mir16-Dotap 26.98±2. pg/ml, p<0.01) and IL-6 (103.83±7pg/ml vs. 37.01±1 pg/ml mir16-Dotap, p<0.05) in the supernatant. To show that the release of pro-inflammatory cytokines by miR-29a is through the TLR7 pathway, we repeated the experiment using DCs isolated from TLR7-/- mice, and saw no upregulation of activation/maturation markers and no release of pro-inflammatory cytokines. Interestingly, B6D2F1 dendritic cells stimulated with miR-29a elicited a stronger alloreactive proliferative response from CFSE labeled B6 T cells as opposed to control treated DCs underscoring the importance of miR-29a in driving an alloreactive response. Summary/Conclusion: Our results indicate that serum miR-29a is up-regulated during aGVHD and activates DCs, likely by direct binding to TLR7/8. NFkB activation by miR-29a results in the release of TNF-a and IL-6 and elicits a stronger allo-reactive T cell proliferative response.
    Full-text · Conference Paper · Jun 2014
  • Bhavana Bhatnagar · Ramiro Garzon
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    ABSTRACT: The discovery and application of advanced molecular techniques, such as gene and microRNA expression profiling, whole genome and exome sequencing, proteomic analysis and methylation assays, have allowed for the identification of recurrent molecular abnormalities in acute myeloid leukemia (AML) that have revolutionized our understanding of the genetic landscape of the disease. These modalities have emerged as valuable tools that permit a more comprehensive and detailed molecular characterization of AML. Many of these molecular abnormalities have been shown to predict prognosis, particularly within the context of cytogenetically normal AML. This review will discuss the major techniques and platforms that have been used to identify novel recurrent gene mutations in AML and briefly describe how these discoveries have impacted on outcome prediction.
    No preview · Article · Mar 2014 · Current Hematologic Malignancy Reports
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    Anjali Mishra · Ramiro Garzon
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    ABSTRACT: In this issue of Blood, Ito et al demonstrate pathogenic implications of microRNA-150 (miR-150) repression in an aggressive form of cutaneous T-cell lymphoma (CTCL). Noncoding RNAs, such as microRNA, profoundly influence gene transcription and protein translation machinery to change hematopoietic cell fate in physiologic and pathologic conditions.
    Preview · Article · Mar 2014 · Blood
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    ABSTRACT: Nucleophosmin mutated AML (NPM1mut-AML) patients have a high rate of complete remission (CR) to induction chemotherapy. However, the mechanisms responsible for such effects are unknown. Since miR-10 family members are expressed at high levels in NPM1mut-AML, we evaluated whether these microRNAs could predict chemotherapy response in AML. We found that high baseline miR-10 family expression in 54 untreated cytogenetically heterogeneous AML patients was associated with achieving CR. However, when we included NPM1 mutation status in the multivariable model, there was a significant interaction effect between miR-10a-5p expression and NPM1 mutation status. Similar results were observed when using a second cohort of 183 cytogenetically normal older (age≥60 years) AML patients. Loss and gain of function experiments using miR-10a-5p in cell lines and primary blasts did not demonstrate any effect in apoptosis or cell proliferation at baseline or after chemotherapy. These data support a bystander role for the miR-10 family in NPM1mut-AML.
    Full-text · Article · Mar 2014 · Blood
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    ABSTRACT: Aberrant expression of the secreted protein, acidic, cysteine-rich (osteonectin) (SPARC) gene, which encodes a matricellular protein that participates in normal tissue remodeling, is associated with a variety of diseases including cancer, but the contribution of SPARC to malignant growth remains controversial. We previously reported that SPARC was among the most upregulated genes in cytogenetically normal acute myeloid leukemia (CN-AML) patients with gene-expression profiles predictive of unfavorable outcome, such as mutations in isocitrate dehydrogenase 2 (IDH2-R172) and overexpression of the oncogenes brain and acute leukemia, cytoplasmic (BAALC) and v-ets erythroblastosis virus E26 oncogene homolog (ERG). In contrast, SPARC was downregulated in CN-AML patients harboring mutations in nucleophosmin (NPM1) that are associated with favorable prognosis. Based on these observations, we hypothesized that SPARC expression is clinically relevant in AML. Here, we found that SPARC overexpression is associated with adverse outcome in CN-AML patients and promotes aggressive leukemia growth in murine models of AML. In leukemia cells, SPARC expression was mediated by the SP1/NF-κB transactivation complex. Furthermore, secreted SPARC activated the integrin-linked kinase/AKT (ILK/AKT) pathway, likely via integrin interaction, and subsequent β-catenin signaling, which is involved in leukemia cell self-renewal. Pharmacologic inhibition of the SP1/NF-κB complex resulted in SPARC downregulation and leukemia growth inhibition. Together, our data indicate that evaluation of SPARC expression has prognosticative value and SPARC is a potential therapeutic target for AML.
    Full-text · Article · Mar 2014 · The Journal of clinical investigation
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    ABSTRACT: Molecular risk stratification of acute myeloid leukemia (AML) is largely based on genetic markers. However, epigenetic changes, including DNA methylation, deregulate gene expression and may also have prognostic impact. We evaluated the clinical relevance of integrating DNA methylation and genetic information in AML. Next-generation sequencing analysis of methylated DNA identified differentially methylated regions (DMRs) associated with prognostic mutations in older (≥ 60 years) cytogenetically normal (CN) patients with AML (n = 134). Genes with promoter DMRs and expression levels significantly associated with outcome were used to compute a prognostic gene expression weighted summary score that was tested and validated in four independent patient sets (n = 355). In the training set, we identified seven genes (CD34, RHOC, SCRN1, F2RL1, FAM92A1, MIR155HG, and VWA8) with promoter DMRs and expression associated with overall survival (OS; P ≤ .001). Each gene had high DMR methylation and lower expression, which were associated with better outcome. A weighted summary expression score of the seven gene expression levels was computed. A low score was associated with a higher complete remission (CR) rate and longer disease-free survival and OS (P < .001 for all end points). This was validated in multivariable models and in two younger (< 60 years) and two older independent sets of patients with CN-AML. Considering the seven genes individually, the fewer the genes with high expression, the better the outcome. Younger and older patients with no genes or one gene with high expression had the best outcomes (CR rate, 94% and 87%, respectively; 3-year OS, 80% and 42%, respectively). A seven-gene score encompassing epigenetic and genetic prognostic information identifies novel AML subsets that are meaningful for treatment guidance.
    No preview · Article · Dec 2013 · Journal of Clinical Oncology
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    ABSTRACT: The success of tyrosine kinase inhibitors (TKIs) in treating chronic myeloid leukemia (CML) depends on the requirement for BCR-ABL1 kinase activity in CML progenitors. However, CML quiescent HSCs are TKI resistant and represent a BCR-ABL1 kinase-independent disease reservoir. Here we have shown that persistence of leukemic HSCs in BM requires inhibition of the tumor suppressor protein phosphatase 2A (PP2A) and expression - but not activity - of the BCR-ABL1 oncogene. Examination of HSCs from CML patients and healthy individuals revealed that PP2A activity was suppressed in CML compared with normal HSCs. TKI-resistant CML quiescent HSCs showed increased levels of BCR-ABL1, but very low kinase activity. BCR-ABL1 expression, but not kinase function, was required for recruitment of JAK2, activation of a JAK2/β-catenin survival/self-renewal pathway, and inhibition of PP2A. PP2A-activating drugs (PADs) markedly reduced survival and self-renewal of CML quiescent HSCs, but not normal quiescent HSCs, through BCR-ABL1 kinase-independent and PP2A-mediated inhibition of JAK2 and β-catenin. This led to suppression of human leukemic, but not normal, HSC/progenitor survival in BM xenografts and interference with long-term maintenance of BCR-ABL1-positive HSCs in serial transplantation assays. Targeting the JAK2/PP2A/β-catenin network in quiescent HSCs with PADs (e.g., FTY720) has the potential to treat TKI-refractory CML and relieve lifelong patient dependence on TKIs.
    Full-text · Article · Sep 2013 · The Journal of clinical investigation

  • No preview · Article · Sep 2013 · Clinical Lymphoma, Myeloma and Leukemia

Publication Stats

11k Citations
975.55 Total Impact Points


  • 2006-2015
    • The Ohio State University
      • • Department of Internal Medicine
      • • Division of Hematology
      • • Department of Molecular Virology, Immunology and Medical Genetics
      Columbus, Ohio, United States
  • 2014
    • Columbus State University
      Columbus, Georgia, United States
  • 2010
    • Duke University
      Durham, North Carolina, United States
  • 2008
    • Sapienza University of Rome
      • Department of Cellular Biotechnology and Hematology BCE
      Roma, Latium, Italy
  • 2005
    • Thomas Jefferson University
      Filadelfia, Pennsylvania, United States