Retained functional normal and preleukemic HSCs at diagnosis are associated to good prognosis in DNMT3Amut NPM1mut AMLs.
Elisa DonatoNadia C CorreiaCarolin AndresenDarja KarpovaRoberto WürthCorinna KleinMarkus SohnAdriana PrzybyllaPetra ZeisbergerKathrin RothfelderHelmut R SalihHalvard BonigSebastian StasikChristoph RölligAnna DolnikLars BullingerFrank BuchholzChristian ThiedeDaniel HübschmannAndreas TrumppPublished in: Blood advances (2022)
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.
Keyphrases
- acute myeloid leukemia
- stem cells
- nk cells
- bone marrow
- allogeneic hematopoietic stem cell transplantation
- flow cytometry
- type diabetes
- newly diagnosed
- metabolic syndrome
- induced apoptosis
- adipose tissue
- cell death
- acute lymphoblastic leukemia
- intensive care unit
- prognostic factors
- endoplasmic reticulum stress
- skeletal muscle
- fatty acid
- extracorporeal membrane oxygenation
- chronic kidney disease
- pi k akt