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Cellular origin of prognostic chromosomal aberrations in AML patients

Leukemia volume 29, pages 1785–1789 (2015)Cite this article

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Acute myeloid leukemia (AML) represents an aggressive cancer entity, whose malignant cells respond abnormally to regulatory stimuli and have lost the ability to differentiate and become fully mature blood cells.1, 2 AML evolves through accumulation of independent genetic aberrations, including chromosomal structural rearrangements and single nucleotide variants (SNVs). Conventional AML diagnostics and recent seminal next-generation sequencing (NGS) studies have identified more than 200 recurrent genetic aberrations presenting in various combinations in individual patients.1, 3, 4, 5, 6, 7 Significantly, many of these aberrations occur in normal hematopoietic stem and progenitor cells (HSCs/HPCs) before definitive leukemic transformation through additional acquisition of a few (that is, mostly 1 or 2) leukemia-promoting driver aberrations.5 NGS studies on sorted bone marrow (BM) populations of AML patients with a normal karyotype have demonstrated the presence of prognostic driver aberrations (that is, NPM1, FLT3-ITD and FLT3-TKD) in committed HPCs but not in multipotent HSCs.8, 9, 10 However, the HSC populations lacking the prognostic driver aberrations contained preleukemic clones harboring a series of recurrent molecular aberrations that were present in the fully transformed committed HPCs together with the prognostic driver aberration.8, 10, 11 Adding to this vast heterogeneity and complexity of AML genomes and their clonal evolution, a recent study of a murine AML model demonstrated that t(9;11) AML originating from HSCs responded poorly to in vivo chemotherapy treatment as compared with t(9;11) AML originating from HPCs.12

Hence, recent advances in genetics support that AML is initiated and sustained by a few aberrations that, in concert with their cellular origin, define the leukemic phenotype of AML patients and ultimately clinical outcome following conventional chemotherapy.

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Acknowledgements

This work was supported by grants from the Danish Council for Strategic Research (grant numbers 09-065157 BTP, 10-092798 BTP and 133100153 KT-M), the Danish Cancer Society (grant number R72-A4572-13-S2, KT-M), the Novo Nordisk Foundation (grant number 34220, KT-M), the Lundbeck Foundation (grant number 29367, KT-M) and through a center grant from the Novo Nordisk Foundation (The Novo Nordisk Foundation Section for Stem Cell Biology in Human Disease, BTP). This work is based on the joint research activities under the framework of the European Program for Cooperation in Science and Technology (COST, Action BM0801, WG1). LB was supported in part by the Deutsche Forschungsgemeinschaft (Heisenberg-Stipendium BU 1339/3-1) and KT-M is supported by a clinical research fellowship from the Novo Nordisk Foundation (grant number 100191).

Author Contributions

HM-J, JJ, NR, NB, BTP and KT-M conceived and designed the study; NB, LB, MKA and AR provided BM samples; HM-J, JJ, MKA and KT-M collected and assembled the data; HM-J, JJ, NR, FOB, OW, NB, BTP and KT-M analyzed and interpreted the data; KT-M drafted the manuscript. HM-J, JJ, NR, MKA, LB, NB and BTP contributed to the writing of the manuscript.

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Author notes

  1. H Mora-Jensen, J Jendholm and N Rapin: Shared first authorship.

  2. B T Porse and K Theilgaard-Mönch: Shared last authorship.

Authors and Affiliations

  1. Department of Hematology, The Granulocyte Research Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark

    H Mora-Jensen & N Borregaard

  2. The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark

    J Jendholm, N Rapin, F O Bagger, B T Porse & K Theilgaard-Mönch

  3. Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark

    J Jendholm, N Rapin, F O Bagger, O Winther, B T Porse & K Theilgaard-Mönch

  4. Danish Stem Cell Centre (DanStem) Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark

    J Jendholm, N Rapin, F O Bagger & B T Porse

  5. Department of Biology, The Bioinformatics Centre, Faculty of Natural Sciences, University of Copenhagen, Copenhagen, Denmark

    N Rapin, F O Bagger & O Winther

  6. The Cytogenetic Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark

    M K Andersen

  7. Department of Hematology, Aarhus University Hospital, University of Aarhus, Aarhus, Denmark

    A S Roug

  8. Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany

    L Bullinger

  9. DTU Compute, Technical University of Denmark, Lyngby, Denmark

    O Winther

  10. Department of Hematology, Skanes University Hospital, University of Lund, Lund, Sweden

    K Theilgaard-Mönch

Authors
  1. H Mora-Jensen
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  11. K Theilgaard-Mönch
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Corresponding author

Correspondence to K Theilgaard-Mönch.

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The authors declare no conflict of interest.

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Mora-Jensen, H., Jendholm, J., Rapin, N. et al. Cellular origin of prognostic chromosomal aberrations in AML patients. Leukemia 29, 1785–1789 (2015). https://doi.org/10.1038/leu.2015.30

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