Cellular origin of prognostic chromosomal aberrations in AML patients

H. Mora-Jensen, J. Jendholm, N. Rapin, M. K. Andersen, A. S. Roug, F. O. Bagger, L. Bullinger, Ole Winther, N. Borregaard, B. T. Porse, K. Theilgaard-Mönch

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

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. 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. 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. 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. 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.
Original languageEnglish
JournalLeukemia
Volume29
Issue number8
Pages (from-to)1785-1789
ISSN0887-6924
DOIs
Publication statusPublished - 2015

Keywords

  • ONCOLOGY
  • HEMATOLOGY
  • ACUTE MYELOID-LEUKEMIA
  • IDENTIFICATION
  • MUTATIONS
  • EVOLUTION
  • CANCER
  • CELLS

Cite this

Mora-Jensen, H., Jendholm, J., Rapin, N., Andersen, M. K., Roug, A. S., Bagger, F. O., ... Theilgaard-Mönch, K. (2015). Cellular origin of prognostic chromosomal aberrations in AML patients. Leukemia, 29(8), 1785-1789. https://doi.org/10.1038/leu.2015.30
Mora-Jensen, H. ; Jendholm, J. ; Rapin, N. ; Andersen, M. K. ; Roug, A. S. ; Bagger, F. O. ; Bullinger, L. ; Winther, Ole ; Borregaard, N. ; Porse, B. T. ; Theilgaard-Mönch, K. / Cellular origin of prognostic chromosomal aberrations in AML patients. In: Leukemia. 2015 ; Vol. 29, No. 8. pp. 1785-1789.
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title = "Cellular origin of prognostic chromosomal aberrations in AML patients",
abstract = "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. 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. 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. 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. 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.",
keywords = "ONCOLOGY, HEMATOLOGY, ACUTE MYELOID-LEUKEMIA, IDENTIFICATION, MUTATIONS, EVOLUTION, CANCER, CELLS",
author = "H. Mora-Jensen and J. Jendholm and N. Rapin and Andersen, {M. K.} and Roug, {A. S.} and Bagger, {F. O.} and L. Bullinger and Ole Winther and N. Borregaard and Porse, {B. T.} and K. Theilgaard-M{\"o}nch",
year = "2015",
doi = "10.1038/leu.2015.30",
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Mora-Jensen, H, Jendholm, J, Rapin, N, Andersen, MK, Roug, AS, Bagger, FO, Bullinger, L, Winther, O, Borregaard, N, Porse, BT & Theilgaard-Mönch, K 2015, 'Cellular origin of prognostic chromosomal aberrations in AML patients', Leukemia, vol. 29, no. 8, pp. 1785-1789. https://doi.org/10.1038/leu.2015.30

Cellular origin of prognostic chromosomal aberrations in AML patients. / Mora-Jensen, H.; Jendholm, J.; Rapin, N.; Andersen, M. K.; Roug, A. S.; Bagger, F. O.; Bullinger, L.; Winther, Ole; Borregaard, N.; Porse, B. T.; Theilgaard-Mönch, K.

In: Leukemia, Vol. 29, No. 8, 2015, p. 1785-1789.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Cellular origin of prognostic chromosomal aberrations in AML patients

AU - Mora-Jensen, H.

AU - Jendholm, J.

AU - Rapin, N.

AU - Andersen, M. K.

AU - Roug, A. S.

AU - Bagger, F. O.

AU - Bullinger, L.

AU - Winther, Ole

AU - Borregaard, N.

AU - Porse, B. T.

AU - Theilgaard-Mönch, K.

PY - 2015

Y1 - 2015

N2 - 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. 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. 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. 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. 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.

AB - 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. 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. 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. 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. 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.

KW - ONCOLOGY

KW - HEMATOLOGY

KW - ACUTE MYELOID-LEUKEMIA

KW - IDENTIFICATION

KW - MUTATIONS

KW - EVOLUTION

KW - CANCER

KW - CELLS

U2 - 10.1038/leu.2015.30

DO - 10.1038/leu.2015.30

M3 - Journal article

VL - 29

SP - 1785

EP - 1789

JO - Leukemia

JF - Leukemia

SN - 0887-6924

IS - 8

ER -

Mora-Jensen H, Jendholm J, Rapin N, Andersen MK, Roug AS, Bagger FO et al. Cellular origin of prognostic chromosomal aberrations in AML patients. Leukemia. 2015;29(8):1785-1789. https://doi.org/10.1038/leu.2015.30