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MMRN1) As Novel Adverse Marker in Pediatric Acute Myeloid Leukemia: a Report from the Children's Oncology Group George S

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MMRN1) As Novel Adverse Marker in Pediatric Acute Myeloid Leukemia: a Report from the Children's Oncology Group George S Published OnlineFirst March 30, 2015; DOI: 10.1158/1078-0432.CCR-14-2684 Personalized Medicine and Imaging Clinical Cancer Research Multimerin-1 (MMRN1) as Novel Adverse Marker in Pediatric Acute Myeloid Leukemia: A Report from the Children's Oncology Group George S. Laszlo1, Todd A. Alonzo2,3, Chelsea J. Gudgeon1, Kimberly H. Harrington1, Robert B. Gerbing3, Yi-Cheng Wang3, Rhonda E. Ries1, Susana C. Raimondi3,4, Betsy A. Hirsch3,5, Alan S. Gamis3,6, Soheil Meshinchi1,3,7, and Roland B. Walter1,8,9 Abstract Purpose: Exploratory gene expression array analyses sug- (67% vs. 77%, P ¼ 0.006), and more frequently had minimal gested multimerin-1 (MMRN1) to be a predictive biomarker in residual disease (43% vs. 24%, P ¼ 0.001) after one induction acute myelogenous leukemia (AML). Following up on these course. They had inferior overall survival (OS; 44% Æ 9% vs. 69% studies, we evaluated the role of MMRN1 expression as out- Æ 4% at 5 years; P < 0.001) and EFS (32% Æ 8% vs. 54% Æ 4% at come predictor in two recent Children's Oncology Group 5 years; P < 0.001) and higher relapse risk (57% Æ 10% vs. trials. 35% Æ 5% at 5 years; P < 0.001). These differences were partly Experimental Design: We retrospectively quantified MMRN1 attributable to the fact that patients with high MMRN1 expres- expression in 183 participants of AAML03P1 and 750 parti- sion less likely had cytogenetic/molecular low-risk disease cipants of AAML0531 by reverse-transcriptase PCR and corre- (P < 0.001) than those with low MMRN1 expression. Neverthe- lated expression levels with disease characteristics and clinical less, after multivariable adjustment, high MMRN1 expression outcome. remained statistically significantly associated with shorter OS Results: In AAML03P1, the highest quartile of MMRN1 expres- (HR, 1.57; 95% confidence interval, 1.17–2.12; P ¼ 0.003) and sion (expression 0.5 relative to b-glucuronidase; n ¼ 45) was EFS (HR, 1.34; 1.04–1.73; P ¼ 0.025), and higher relapse risk associated with inferior event-free survival (EFS; P < 0.002) and (HR, 1.40; 1.01–1.94; P ¼ 0.044). higher relapse risk (P < 0.004). In AAML0531, in which we Conclusions: Together, our studies identify MMRN1 expres- quantified MMRN1 mRNA for validation, patients with relative sion as a novel biomarker that may refine AML risk stratification. MMRN1 expression 0.5 (n ¼ 160) less likely achieved remission Clin Cancer Res; 21(14); 3187–95. Ó2015 AACR. Introduction are the most important ones and provide the framework for diagnostic classification and risk stratification schemes (1). Acute myelogenous leukemia (AML) is a challenging disease Although such schemes are increasingly used for risk-tailored with outcomes that vary widely between individual patients (1). treatment assignment, there are only a small number of informa- Numerous disease-related risk factors have so far been recognized; tive predictive markers, and it is a recurrent clinical observation among those, cytogenetic abnormalities and somatic mutations that this limited battery fails to accurately predict outcome for many patients. Thus, there remains a need for refined tools to 1Clinical Research Division, Fred Hutchinson Cancer Research Center, characterize disease risk in AML. Our recent studies indicate that Seattle, Washington. 2Department of Biostatistics, University of multimerin-1 (MMRN1) may be such a biomarker. 3 Southern California, Los Angeles, California. Children's Oncology MMRN1, a member of the elastin microfibrillar interface pro- Group, Monrovia, California. 4Department of Pathology, St. Jude Chil- dren's Research Hospital, Memphis, Tennessee. 5Department of Lab- tein (EMILIN)/multimerin family, has so far primarily been oratory Medicine and Pathology, University of Minnesota Cancer Cen- described as a component of secretory granules found in platelets ter, Minneapolis, Minnesota. 6Division of Hematology-Oncology, Chil- and endothelial cells that may mediate cellular adhesion via dren's Mercy Hospitals and Clinics, Kansas City, Missouri. 7Department of Pediatrics, University of Washington, Seattle,Washington. 8Division integrin receptors (2). During recent discovery studies using gene of Hematology, Department of Medicine, University of Washington, expression array data from diagnostic specimens of 211 recently Seattle, Washington. 9Department of Epidemiology, University of treated pediatric AML patients, we identified MMRN1 as a SOCS2 Washington, Seattle, Washington. (3) cosegregating gene whose expression varied widely (Supple- Note: Supplementary data for this article are available at Clinical Cancer mentary Fig. S1) and appeared to be related to patient out- Research Online (http://clincancerres.aacrjournals.org/). comes (Supplementary Fig. S2). To follow-up on these studies, Corresponding Author: Roland B. Walter, Clinical Research Division, Fred we retrospectively quantified MMRN1 expression in pretreatment Hutchinson Cancer Research Center, 1100 Fairview Avenue North, D2-190, bone marrow specimens from participants of the Children's Seattle, WA 98109-1024. Phone: 206-667-3599; Fax: 206-667-6519; E-mail: Oncology Group (COG) AML protocol, AAML03P1, and then [email protected] validated findings in participants of AAML0531 to investigate the doi: 10.1158/1078-0432.CCR-14-2684 potential role of MMRN1 as a predictive biomarker in pediatric Ó2015 American Association for Cancer Research. AML. www.aacrjournals.org 3187 Downloaded from clincancerres.aacrjournals.org on October 4, 2021. © 2015 American Association for Cancer Research. Published OnlineFirst March 30, 2015; DOI: 10.1158/1078-0432.CCR-14-2684 Laszlo et al. the clinical protocol. IRB approval was obtained from Fred Translational Relevance Hutchinson Cancer Research Center (Seattle, WA) before conduct Although several predictive biomarkers have been described of this biologic study, which was also approved by the COG in acute myelogenous leukemia (AML), current models are Myeloid Disease Biology Committee and the National Cancer unable to accurately forecast therapeutic response and surviv- Institute Cancer Therapy Evaluation Program. al. Exploratory gene expression array analyses suggested that multimerin-1 (MMRN1), a hitherto very poorly described Risk stratification gene that may be involved in cellular adhesion via integrin A combination of cytogenetic and molecular abnormalities was receptors, could be a novel predictive biomarker in AML. used to stratify participants into risk groups. A patient was Following up on these studies, we investigated the MMRN1 considered low-risk if a chromosomal abnormality/mutation was expression in two recent Children's Oncology Group trials, present in core-binding factors [CBF; t(8;21) or inv(16)/t(16;16)], AAML03P1 and AAML0531. While associated with adverse nucleophosmin [NPM1; unless a FLT3-ITD mutation with high disease-risk features, we found that high MMRN1 expression allelic ratio (0.4) was also present], or CCAAT/enhancer-binding was independently associated with shorter overall survival and protein (C/EBP), alpha [CEBPA]; for CEBPA, both single and event-free survival as well as a higher relapse risk in a large set double mutations were considered favorable (6). Patients were of homogenously treated pediatric patients with AML. Togeth- classified as high-risk if they had monosomy 5 or deletion of er, these studies identify MMRN1 expression as a novel bio- 5q (À5/5qÀ), monosomy 7 (À7), or FLT3-ITD with high allelic marker that may refine AML risk stratification. ratio (0.4 or higher). All other patients with data sufficient for classification were considered standard-risk. Detection and quantification of MRD fi Patients and Methods Residual AML was quanti ed in bone marrow aspirates col- lected at the end of the first induction course by multiparameter Patient samples flow cytometry using a "different-from-normal" approach as pre- Cryopreserved pretreatment ("diagnostic") specimens from viously described (7). patients enrolled on AAML03P1 or AAML0531 who consented to the biology studies and had bone marrow samples available Quantification of MMRN1 expression in unsorted AML þ À were included in this study. AAML03P1 (registered at Clinical- specimens and FACS-isolated CD34 /CD33 and þ þ Trials.gov as NCT00070174) was a multicenter phase III pilot CD34 /CD33 cells study that determined the safety and feasibility of adding gemtu- Total RNA from unsorted diagnostic AML specimens was zumab ozogamicin (GO) to intensive chemotherapy among 339 extracted with the AllPrep DNA/RNA Mini Kit using the QIAcube eligible children and adolescents (ages 1 month to 21 years) with automated system (Qiagen). After quantification with a micro- newly diagnosed de novo AML, excluding those with acute pro- volume spectrophotometer (NanoDrop; Thermo Scientific), myelocytic leukemia (APL), bone marrow failure syndromes, 10 ng of total RNA was subjected to qRT-PCR (7900 Real-Time juvenile myelomonocytic leukemia, or Down syndrome between PCR System; Applied Biosystems) using TaqMan primers as per 2003 and 2005 (4). AAML0531 (NCT00372593) was the subse- manufacturer's instructions to determine expression of MMRN1 quent multicenter phase III study that determined the addition of and, for normalization, the housekeeping gene, b-glucuronidase GO to intensive chemotherapy among 1,070 eligible patients ages (GUSB). Primer probe sets were as follows: MMRN1 was designed <30 years with newly diagnosed de novo non-APL AML, excluding to amplify sequence at the junction of exon 3 and 4 and GUSB was those with bone marrow failure syndromes, juvenile myelomo-
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