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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., Correia, N.C., Andresen, C., Karpova, D., Würth, R., Klein, C., Sohn, M., Przybylla, A., Zeisberger, P., Rothfelder, K., Salih, H.R., Bonig, H., Stasik, S., Röllig, C., Dolnik, A., Bullinger, L., Buchholz, F., Thiede, C.D., 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 |
| ISSN: | 2473-9529 |
| Publisher: | American Society of Hematology |
| Volume: | 7 |
| Number: | 6 |
| 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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