Direct evidence for cooperating genetic events in the leukemic transformation of normal human hematopoietic cells

J. K. Warner, J. C.Y. Wang, Katsuto Takenaka, S. Doulatov, J. L. McKenzie, L. Harrington, J. E. Dick

Research output: Contribution to journalArticle

78 Citations (Scopus)

Abstract

Although genetic abnormalities associated with hematological malignancies are readily identified, the natural history of human leukemia cannot be observed because initiating and subsequent transforming events occur before clinical presentation. Furthermore, it has not been possible to study leukemogenesis in vitro as normal human cells do not spontaneously transform. Thus, the nature and sequence of genetic changes required to convert human hematopoietic cells into leukemia cells have never been directly examined. We have developed a system where the first step in the leukemogenic process is an engineered disruption of differentiation and self-renewal due to expression of the TLS-ERG oncogene, followed in some cases by overexpression of hTERT. In two of 13 experiments, transduced cells underwent step-wise transformation and immortalization through spontaneous acquisition of additional changes. The acquired karyotypic abnormalities and alterations including upregulation of Bmi-1 and telomerase all occur in acute myeloid leukemia (AML), establishing the relevance of this system. One resultant cell line studied in depth exhibits cellular properties characteristic of AML, notably a hierarchical organization initiated by leukemic stem cells that differentiate abnormally. These findings provide direct evidence for multiple cooperating events in human leukemogenesis, and provide a foundation for studying the genetic changes that occur during leukemic initiation and progression.

Original languageEnglish
Pages (from-to)1794-1805
Number of pages12
JournalLeukemia
Volume19
Issue number10
DOIs
Publication statusPublished - Jan 1 2005

Fingerprint

Acute Myeloid Leukemia
Leukemia
Telomerase
Hematologic Neoplasms
Oncogenes
Up-Regulation
Stem Cells
Cell Line
In Vitro Techniques

All Science Journal Classification (ASJC) codes

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

Cite this

Warner, J. K., Wang, J. C. Y., Takenaka, K., Doulatov, S., McKenzie, J. L., Harrington, L., & Dick, J. E. (2005). Direct evidence for cooperating genetic events in the leukemic transformation of normal human hematopoietic cells. Leukemia, 19(10), 1794-1805. https://doi.org/10.1038/sj.leu.2403917

Direct evidence for cooperating genetic events in the leukemic transformation of normal human hematopoietic cells. / Warner, J. K.; Wang, J. C.Y.; Takenaka, Katsuto; Doulatov, S.; McKenzie, J. L.; Harrington, L.; Dick, J. E.

In: Leukemia, Vol. 19, No. 10, 01.01.2005, p. 1794-1805.

Research output: Contribution to journalArticle

Warner, JK, Wang, JCY, Takenaka, K, Doulatov, S, McKenzie, JL, Harrington, L & Dick, JE 2005, 'Direct evidence for cooperating genetic events in the leukemic transformation of normal human hematopoietic cells', Leukemia, vol. 19, no. 10, pp. 1794-1805. https://doi.org/10.1038/sj.leu.2403917
Warner JK, Wang JCY, Takenaka K, Doulatov S, McKenzie JL, Harrington L et al. Direct evidence for cooperating genetic events in the leukemic transformation of normal human hematopoietic cells. Leukemia. 2005 Jan 1;19(10):1794-1805. https://doi.org/10.1038/sj.leu.2403917
Warner, J. K. ; Wang, J. C.Y. ; Takenaka, Katsuto ; Doulatov, S. ; McKenzie, J. L. ; Harrington, L. ; Dick, J. E. / Direct evidence for cooperating genetic events in the leukemic transformation of normal human hematopoietic cells. In: Leukemia. 2005 ; Vol. 19, No. 10. pp. 1794-1805.
@article{70f2232bb78347889bf6418c3b362a89,
title = "Direct evidence for cooperating genetic events in the leukemic transformation of normal human hematopoietic cells",
abstract = "Although genetic abnormalities associated with hematological malignancies are readily identified, the natural history of human leukemia cannot be observed because initiating and subsequent transforming events occur before clinical presentation. Furthermore, it has not been possible to study leukemogenesis in vitro as normal human cells do not spontaneously transform. Thus, the nature and sequence of genetic changes required to convert human hematopoietic cells into leukemia cells have never been directly examined. We have developed a system where the first step in the leukemogenic process is an engineered disruption of differentiation and self-renewal due to expression of the TLS-ERG oncogene, followed in some cases by overexpression of hTERT. In two of 13 experiments, transduced cells underwent step-wise transformation and immortalization through spontaneous acquisition of additional changes. The acquired karyotypic abnormalities and alterations including upregulation of Bmi-1 and telomerase all occur in acute myeloid leukemia (AML), establishing the relevance of this system. One resultant cell line studied in depth exhibits cellular properties characteristic of AML, notably a hierarchical organization initiated by leukemic stem cells that differentiate abnormally. These findings provide direct evidence for multiple cooperating events in human leukemogenesis, and provide a foundation for studying the genetic changes that occur during leukemic initiation and progression.",
author = "Warner, {J. K.} and Wang, {J. C.Y.} and Katsuto Takenaka and S. Doulatov and McKenzie, {J. L.} and L. Harrington and Dick, {J. E.}",
year = "2005",
month = "1",
day = "1",
doi = "10.1038/sj.leu.2403917",
language = "English",
volume = "19",
pages = "1794--1805",
journal = "Leukemia",
issn = "0887-6924",
publisher = "Nature Publishing Group",
number = "10",

}

TY - JOUR

T1 - Direct evidence for cooperating genetic events in the leukemic transformation of normal human hematopoietic cells

AU - Warner, J. K.

AU - Wang, J. C.Y.

AU - Takenaka, Katsuto

AU - Doulatov, S.

AU - McKenzie, J. L.

AU - Harrington, L.

AU - Dick, J. E.

PY - 2005/1/1

Y1 - 2005/1/1

N2 - Although genetic abnormalities associated with hematological malignancies are readily identified, the natural history of human leukemia cannot be observed because initiating and subsequent transforming events occur before clinical presentation. Furthermore, it has not been possible to study leukemogenesis in vitro as normal human cells do not spontaneously transform. Thus, the nature and sequence of genetic changes required to convert human hematopoietic cells into leukemia cells have never been directly examined. We have developed a system where the first step in the leukemogenic process is an engineered disruption of differentiation and self-renewal due to expression of the TLS-ERG oncogene, followed in some cases by overexpression of hTERT. In two of 13 experiments, transduced cells underwent step-wise transformation and immortalization through spontaneous acquisition of additional changes. The acquired karyotypic abnormalities and alterations including upregulation of Bmi-1 and telomerase all occur in acute myeloid leukemia (AML), establishing the relevance of this system. One resultant cell line studied in depth exhibits cellular properties characteristic of AML, notably a hierarchical organization initiated by leukemic stem cells that differentiate abnormally. These findings provide direct evidence for multiple cooperating events in human leukemogenesis, and provide a foundation for studying the genetic changes that occur during leukemic initiation and progression.

AB - Although genetic abnormalities associated with hematological malignancies are readily identified, the natural history of human leukemia cannot be observed because initiating and subsequent transforming events occur before clinical presentation. Furthermore, it has not been possible to study leukemogenesis in vitro as normal human cells do not spontaneously transform. Thus, the nature and sequence of genetic changes required to convert human hematopoietic cells into leukemia cells have never been directly examined. We have developed a system where the first step in the leukemogenic process is an engineered disruption of differentiation and self-renewal due to expression of the TLS-ERG oncogene, followed in some cases by overexpression of hTERT. In two of 13 experiments, transduced cells underwent step-wise transformation and immortalization through spontaneous acquisition of additional changes. The acquired karyotypic abnormalities and alterations including upregulation of Bmi-1 and telomerase all occur in acute myeloid leukemia (AML), establishing the relevance of this system. One resultant cell line studied in depth exhibits cellular properties characteristic of AML, notably a hierarchical organization initiated by leukemic stem cells that differentiate abnormally. These findings provide direct evidence for multiple cooperating events in human leukemogenesis, and provide a foundation for studying the genetic changes that occur during leukemic initiation and progression.

UR - http://www.scopus.com/inward/record.url?scp=27144477007&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=27144477007&partnerID=8YFLogxK

U2 - 10.1038/sj.leu.2403917

DO - 10.1038/sj.leu.2403917

M3 - Article

C2 - 16094415

AN - SCOPUS:27144477007

VL - 19

SP - 1794

EP - 1805

JO - Leukemia

JF - Leukemia

SN - 0887-6924

IS - 10

ER -