Page 207 - Haematologica March 2020

Acute Myeloid Leukemia
Mutations associated with a 17-gene leukemia stem cell score and the score’s prognostic relevance in the context of the European LeukemiaNet classification of acute
myeloid leukemia
Ferrata Storti Foundation
Haematologica 2020 Volume 105(3):721-729
Marius Bill,1 Deedra Nicolet,1,2 Jessica Kohlschmidt,1,2 Christopher J. Walker,1 Krzysztof Mrózek,1 Ann-Kathrin Eisfeld,1 Dimitrios Papaioannou,1 Xiaoqing Rong-Mullins,1 Zachary Brannan,1 Jonathan E. Kolitz,3 Bayard L. Powell,4 Kellie J. Archer,1,5 Adrienne M. Dorrance,1,6 Andrew J. Carroll,7 Richard M. Stone,8 John C. Byrd,1,6 Ramiro Garzon1,6 and Clara D. Bloomfield1,6
1The Ohio State University Comprehensive Cancer Center, Columbus, OH; 2Alliance Statistics and Data Center, The Ohio State University Comprehensive Cancer Center, Columbus, OH; 3Monter Cancer Center, Hofstra Northwell School of Medicine, Lake Success, NY; 4Comprehensive Cancer Center of Wake Forest University, Winston-Salem, NC; 5College of Public Health, The Ohio State University, Columbus, OH; 6Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH; 7Department of Genetics, University of Alabama at Birmingham, Birmingham, AL and 8Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
ABSTRACT
Leukemia stem cells (LSC) are more resistant to standard chemotherapy and their persistence during remission can cause relapse, which is still one of the major clinical challenges in the treatment of acute myeloid leukemia (AML). A better understanding of the mutational patterns and the prognostic impact of molecular markers associated with stemness could lead to better clinical management and improve patients’ outcomes. We applied a previously described 17-gene expression score comprising genes differently expressed between LSC and leukemic bulk blasts, for 934 adult patients with de novo AML, and studied associations of the 17-gene LSC score with clinical data and mutation status of 81 genes recurrently mutated in cancer and leukemia. We found that patients with a high 17-gene score were older and had more mutations. The 17-gene score was found to have a prognostic impact in both younger (aged <60 years) and older (aged ≥60 years) patients with AML. We also analyzed the 17-gene LSC score in the context of the 2017 European LeukemiaNet genetic-risk classification and found that for younger patients the score refined the classification, and identified patients currently classified in the European LeukemiaNet Favorable-risk category who had a worse outcome.
Introduction
Acute myeloid leukemia (AML) is a heterogeneous disease.1-3 Although many advances have been made in understanding the biology and treatment of AML, the long-term survival rates are still only ~40% for younger adults (aged <60 years), and ~10-15% for older patients (aged ≥60 years).1-3 One major clinical challenge impeding improved outcome is relapse following achievement of complete remis- sion (CR). It is hypothesized that relapse occurs because of the persistence of leukemia stem cells (LSC) and subsequent outgrowth of the leukemia clone.4-8 Studies on the clinical relevance of LSC are still rare because no LSC-specific phe- notype has been firmly established. Although the percentage of CD34+/CD38-- expressing cells, which were initially assumed to include all LSC, was shown to affect prognosis,9,10 the use of more permissive immunodeficient mouse models revealed that LSC can also be found in the CD34+/CD38+ and CD34- compart- ments.4,7,9,11-15 Instead of using surface markers to identify and quantify the presence
Correspondence:
MARIUS BILL
marius.bill@osumc.edu
CLARA D. BLOOMFIELD
clara.bloomfield@osumc.edu
Received: April 19, 2019. Accepted: August 13, 2019. Pre-published: August 14, 2019.
doi:10.3324/haematol.2019.225003
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/3/721
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haematologica | 2020; 105(3)
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