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Retained functional normal and preleukemic HSCs at diagnosis are associated to good prognosis in DNMT3Amut NPM1mut AMLs

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Item Type:Article
Title:Retained functional normal and preleukemic HSCs at diagnosis are associated to good prognosis in DNMT3Amut NPM1mut AMLs
Creators Name:Donato, E. and Correia, N.C. and Andresen, C. and Karpova, D. and Würth, R. and Klein, C. and Sohn, M. and Przybylla, A. and Zeisberger, P. and Rothfelder, K. and Salih, H.R. and Bonig, H. and Stasik, S. and Röllig, C. and Dolnik, A. and Bullinger, L. and Buchholz, F. and Thiede, C.D. and Hübschmann, D. and Trumpp, A.
Abstract:AML is a heterogeneous disease characterized by high rate of relapse and mortality. While chemotherapies may eradicate blasts, they are less effective in eliminating relapse-causing Leukemic Stem Cells (LSCs). Although LSCs are usually identified as CD34+CD38- cells, there is significant heterogeneity in surface marker expression and CD34- LSCs exist particularly in NPM1mut AMLs. By analyzing diagnostic primary DNMT3AmutNPM1mut AML samples, we suggest a novel flow cytometry sorting strategy particularly useful for CD34neg AML subtypes. To enrich for LSCs independently of CD34 status, positive selection for GPR56 and negative selection for NKG2D-Ligands are employed. We demonstrate that the functional reconstitution capacity of CD34- and CD34+ LSCs as well as their transcriptomes are very similar supporting phenotypic plasticity. Furthermore, we show that while CD34+ subpopulations can contain next to LSCs also normal and/or pre-leukemic Hematopoietic Stem Cells (HSCs), this is not the case in CD34-GPR56+NKG2DL- enriched LSCs which thus can be isolated with high purity. Finally, we show that AML patients, who retain at time of diagnosis a reserve of normal and/or preleukemic HSCs in their bone marrow able to reconstitute immunocompromised mice, have significant longer relapse-free and overall survival compared to AML patients in whom functional HSCs are no longer detectable.
Keywords:AML, LSC, Normal/Pre-Leukemic HSCs, DNMT3A, NPM1, Animals, Mice
Source:Blood Advances
Publisher:American Society of Hematology
Page Range:1011-1018
Date:28 March 2023
Official Publication:https://doi.org/10.1182/bloodadvances.2022008497
PubMed:View item in PubMed

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