A murine model of CML blast crisis induced by cooperation between BCR/ABL and NUP98/HOXA9

Ajeeta B Dash; Ifor R Williams; Jeffery L Kutok; Michael H Tomasson; Ema Anastasiadou; Kathleen Lindahl; Shaoguang Li; Richard A Van Etten; Julian Borrow; David Housman; Brian Druker; D Gary Gilliland

doi:10.1073/pnas.102583199

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A murine model of CML blast crisis induced by cooperation between BCR/ABL and NUP98/HOXA9

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A murine model of CML blast crisis induced by cooperation between BCR/ABL and NUP98/HOXA9

Ajeeta B Dash, Ifor R Williams, Jeffery L Kutok, Michael H Tomasson, Ema Anastasiadou, Kathleen Lindahl, Shaoguang Li, Richard A Van Etten, Julian Borrow, David Housman, …

Proceedings of the National Academy of Sciences - PNAS, Vol.99(11), pp.7622-7627

05/28/2002

DOI: 10.1073/pnas.102583199

PMCID: PMC124303

PMID: 12032333

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Abstract

Constitutive activation of tyrosine kinases, such as the BCR/ABL fusion associated with t(9;22)(q34;q22), is a hallmark of chronic myeloid leukemia (CML) syndromes in humans. Expression of BCR/ABL is both necessary and sufficient to cause a chronic myeloproliferative syndrome in murine bone marrow transplantation models, and absolutely depends on kinase activity. Progression of CML to acute leukemia (blast crisis) in humans has been associated with acquisition of secondary chromosomal translocations, including the t(7;11)(p15;p15) resulting in the NUP98/HOXA9 fusion protein. We demonstrate that BCR/ABL cooperates with NUP98/HOXA9 to cause blast crisis in a murine model. The phenotype depends both on expression of BCR/ABL and NUP98/HOXA9, but tumors retain sensitivity to the ABL inhibitor STI571 in vitro and in vivo. This paradigm is applicable to other constitutively activated tyrosine kinases such as TEL/PDGFbetaR. These experiments document cooperative effects between constitutively activated tyrosine kinases, which confer proliferative and survival properties to hematopoietic cells, with mutations that impair differentiation, such as the NUP98/HOXA9, giving rise to the acute myeloid leukemia (AML) phenotype. Furthermore, these data indicate that despite acquisition of additional mutations, CML blast crisis cells retain their dependence on BCR/ABL for proliferation and survival.

Green Fluorescent Proteins

Blast Crisis - pathology

Humans

Bone Marrow Cells - pathology

Pyrimidines - pharmacology

Imatinib Mesylate

Piperazines - pharmacology

Disease Progression

Homeodomain Proteins - genetics

Nuclear Pore Complex Proteins - genetics

Fusion Proteins, bcr-abl - genetics

Animals

Proviruses - genetics

Oncogene Proteins, Fusion - genetics

Cell Division

Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology

Bone Marrow Transplantation

Cloning, Molecular

Luminescent Proteins - genetics

Antineoplastic Agents - pharmacology

Mice

Benzamides

Tumor Cells, Cultured

Disease Models, Animal

Details

Title: Subtitle: A murine model of CML blast crisis induced by cooperation between BCR/ABL and NUP98/HOXA9
Creators: Ajeeta B Dash - Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
Ifor R Williams
Jeffery L Kutok
Michael H Tomasson
Ema Anastasiadou
Kathleen Lindahl
Shaoguang Li
Richard A Van Etten
Julian Borrow
David Housman
Brian Druker
D Gary Gilliland
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.99(11), pp.7622-7627
DOI: 10.1073/pnas.102583199
PMID: 12032333
PMCID: PMC124303
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: National Academy of Sciences
Grant note: AR44268 / NIAMS NIH HHS DK50654 / NIDDK NIH HHS P01 CA066996 / NCI NIH HHS P01 DK050654 / NIDDK NIH HHS CA66996 / NCI NIH HHS
Language: English
Date published: 05/28/2002
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
Record Identifier: 9984094678802771

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