4.6 Article

Retained functional normal and preleukemic HSCs at diagnosis are associated with good prognosis in DNMT3AmutNPM1mut AMLs

Journal

BLOOD ADVANCES
Volume 7, Issue 6, Pages 1011-1018

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ELSEVIER
DOI: 10.1182/bloodadvances.2022008497

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This study proposes a novel flow cytometry sorting strategy for CD34 neg AML subtypes, enriching for leukemic stem cells (LSCs) independently of CD34 status by positive selection for GPR56 and negative selection for NKG2D ligands. The functional reconstitution capacity and transcriptomes of CD34- and CD34+ LSCs are shown to be similar, supporting the concept of phenotypic plasticity. Patients with AML who still retain functional hematopoietic stem cells (HSCs) at the time of diagnosis have longer relapse-free and overall survival.
Acute myeloid leukemia (AML) is a heterogeneous disease characterized by high rate of relapse and mortality. Current chemotherapies whilst successful in eradicating blasts, 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 used. We show that the functional reconstitution capacity of CD34- and CD34+ LSCs as well as their transcriptomes are very similar which support phenotypic plasticity. Furthermore, we show that although CD34+ subpopulations can contain next to LSCs also normal and/or preleukemic hematopoietic stem cells (HSCs), this is not the case in CD34-GPR56+NKG2DLenriched LSCs which thus can be isolated with high purity. Finally, we show that patients with AML, who retain at the time of diagnosis a reserve of normal and/or preleukemic HSCs in their bone marrow able to reconstitute immunocompromised mice, have significantly longer relapse-free and overall survival than patients with AML in whom functional HSCs are no longer detectable.

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