Instability of BCRABL Gene in Primary and Cultured Chronic Myeloid Leukemia Stem Cells
Identifieur interne : 002509 ( Main/Exploration ); précédent : 002508; suivant : 002510Instability of BCRABL Gene in Primary and Cultured Chronic Myeloid Leukemia Stem Cells
Auteurs : Xiaoyan Jiang [Canada] ; Kyi Min Saw [Canada] ; Allen Eaves [Canada] ; Connie Eaves [Canada]Source :
- Journal of the National Cancer Institute [ 0027-8874 ] ; 2007.
Abstract
Background Imatinib mesylate treatment causes remissions in a majority of patients with chronic myeloid leukemia (CML), but relapses are an increasing problem. We hypothesized that imatinib-resistant leukemic cells emerge from CML stem cells that acquire BCRABL gene mutations even before exposure to BCRABLtargeted agents such as imatinib. Methods Lineage-negative (i.e., immature) CD34CD38 CML stem cellenriched populations were isolated from five patients with chronic phase CML samples by fluorescence-activated cell sorting. To identify BCRABL gene mutations, complementary DNAs (cDNAs) prepared from purified CML stem cells were subjected to allele-specific amplification using primers corresponding to 16 kinase domain mutations, with normal bone marrow cells serving as negative controls. We also cloned and directly sequenced BCRABL cDNAs prepared from freshly isolated CML stem cells and from their progeny generated after 35 weeks of culture. Results In 20%33% of cDNA preparations from freshly isolated CML stem cellenriched populations, both allele-specific amplification and direct sequencing methods revealed mutations in sequences corresponding to the BCRABL kinase domain. Mutations were not observed in cDNA sequences encoding the c-ABL kinase domain that were obtained from similar types of primitive normal cells. More than 70 different BCRABL mutations (including frameshift mutations and premature stop codons) were identified in the progeny of cultured CML stem cells. Analysis of individual clones derived from the cultured cells demonstrated that new BCRABL mutations were produced. Conclusions Primary CML stem cells display instability of the BCRABL fusion gene both in vivo and in vitro. Thus, patients may possess leukemic stem cells with BCRABL kinase mutations before initiation of BCRABLtargeted therapies and would likely be predisposed to develop resistance to these agents.
Url:
DOI: 10.1093/jnci/djk150
Affiliations:
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We hypothesized that imatinib-resistant leukemic cells emerge from CML stem cells that acquire BCRABL gene mutations even before exposure to BCRABLtargeted agents such as imatinib. Methods Lineage-negative (i.e., immature) CD34CD38 CML stem cellenriched populations were isolated from five patients with chronic phase CML samples by fluorescence-activated cell sorting. To identify BCRABL gene mutations, complementary DNAs (cDNAs) prepared from purified CML stem cells were subjected to allele-specific amplification using primers corresponding to 16 kinase domain mutations, with normal bone marrow cells serving as negative controls. We also cloned and directly sequenced BCRABL cDNAs prepared from freshly isolated CML stem cells and from their progeny generated after 35 weeks of culture. Results In 20%33% of cDNA preparations from freshly isolated CML stem cellenriched populations, both allele-specific amplification and direct sequencing methods revealed mutations in sequences corresponding to the BCRABL kinase domain. Mutations were not observed in cDNA sequences encoding the c-ABL kinase domain that were obtained from similar types of primitive normal cells. More than 70 different BCRABL mutations (including frameshift mutations and premature stop codons) were identified in the progeny of cultured CML stem cells. Analysis of individual clones derived from the cultured cells demonstrated that new BCRABL mutations were produced. Conclusions Primary CML stem cells display instability of the BCRABL fusion gene both in vivo and in vitro. Thus, patients may possess leukemic stem cells with BCRABL kinase mutations before initiation of BCRABLtargeted therapies and would likely be predisposed to develop resistance to these agents.</div></front></TEI><affiliations><list><country><li>Canada</li></country></list><tree><country name="Canada"><noRegion><name sortKey="Jiang, Xiaoyan" sort="Jiang, Xiaoyan" uniqKey="Jiang X" first="Xiaoyan" last="Jiang">Xiaoyan Jiang</name></noRegion><name sortKey="Eaves, Allen" sort="Eaves, Allen" uniqKey="Eaves A" first="Allen" last="Eaves">Allen Eaves</name><name sortKey="Eaves, Connie" sort="Eaves, Connie" uniqKey="Eaves C" first="Connie" last="Eaves">Connie Eaves</name><name sortKey="Jiang, Xiaoyan" sort="Jiang, Xiaoyan" uniqKey="Jiang X" first="Xiaoyan" last="Jiang">Xiaoyan Jiang</name><name sortKey="Saw, Kyi Min" sort="Saw, Kyi Min" uniqKey="Saw K" first="Kyi Min" last="Saw">Kyi Min Saw</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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