The influence of mutational status and biological characteristics of acute myeloid leukemia on xenotransplantation outcomes in NOD SCID gamma mice
- 173 Downloads
This study aimed at analyzing the association of gene mutations and other acute myeloid leukemia (AML) characteristics with engraftment outcomes in immunodeficient mice and to select the engraftment outcomes that best reflect patient survival.
Mutations in 19 genes as well as leukemia- and patient-related characteristics were analyzed for a group of 47 de novo AML samples with respect to three engraftment outcomes: engraftment ability, engraftment intensity (percentage of hCD45+ cells) and engraftment latency. Leukemia-related characteristics were additionally analyzed in an extended group of 68 samples that included the 47 de novo samples, and additional 21 samples from refractory and relapsed cases. Engraftment outcomes were compared with overall and event-free survival of the patients.
For the 47 de novo samples, no single mutation influenced engraftment, whereas the NPM1 mut /DNMT3A mut co-mutation was associated with higher engraftment ability. NPM1 mut /FLT3-ITD neg had lower engraftment intensity. Among leukemia-related characteristics, a complex karyotype was associated with higher engraftment intensity. Among patient-related characteristics, higher cytogenetic risk was associated with higher engraftment intensity, and failure to achieve clinical remission was associated with shorter engraftment latency. In the extended group of 68 samples, white blood count was associated with higher engraftment ability, and the presence of a complex karyotype was associated with higher engraftment intensity. Association with patient overall survival was seen only for engraftment intensity.
The engraftment of AML was influenced by mutation-interactions and other AML characteristics, rather than by single mutated genes, and engraftment intensity best reflected clinical penetrance of AML.
KeywordsAML Engraftment NOD SCID gamma Mutations Sequencing
This study was supported by funds from the Faculty of Medicine MU to junior researcher Martin Culen. Supported by Ministry of Health of the Czech Republic, Grant No. 15-25809A. All rights reserved. Supported by MUNI/A/0968/2017.
Compliance with ethical standards
Conflict of interest
All authors declare that they have no conflicts of interest.
Samples were collected from AML patients treated at the University Hospital, Brno. Informed consent was obtained from all individual participants included in the study. The study was approved by the Institutional Review Board of the University Hospital, Brno. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. All animal experiments were approved by institutional review board of the Masaryk University, Brno, and performed in accordance with all European guidelines for the protection of laboratory animals.
- Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, Bloomfield CD, Cazzola M, Vardiman JW (2016) The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127:2391–2405. https://doi.org/10.1182/blood-2016-03-643544 CrossRefPubMedGoogle Scholar
- Kennedy JA, Mitchell A, Chen WC, McLeod J, Popescu AC, Arruda A, Minden MD, Dick JE, Wang JCY (2013) Leukemic engraftment In NOD.SCID mice is correlated with clinical parameters and predicts outcome in human AML. Blood 122:50Google Scholar
- Risueno RM, Campbell CJV, Dingwall S, Levadoux-Martin M, Leber B, Xenocostas A, Bhatia M (2011) Identification of T-lymphocytic leukemia-initiating stem cells residing in a small subset of patients with acute myeloid leukemic disease. Blood 117:7112–7120. https://doi.org/10.1182/blood-2011-01-329078 CrossRefPubMedGoogle Scholar
- Taussig DC, Pearce DJ, Simpson C, Rohatiner AZ, Lister TA, Kelly G, Luongo JL, Danet-Desnoyers GA, Bonnet D (2005) Hematopoietic stem cells express multiple myeloid markers: implications for the origin and targeted therapy of acute myeloid leukemia. Blood 106:4086–4092. https://doi.org/10.1182/blood-2005-03-1072 CrossRefPubMedPubMedCentralGoogle Scholar
- Zeijlemaker W, Kelder A, Wouters R, Valk PJ, Witte BI, Cloos J, Ossenkoppele GJ, Schuurhuis GJ (2015) Absence of leukaemic CD34(+) cells in acute myeloid leukaemia is of high prognostic value: a longstanding controversy deciphered. Br J Haematol. https://doi.org/10.1111/bjh.13572 PubMedCrossRefGoogle Scholar