Use of chromosome engineering to model a segmental deletion of chromosome band 7q22 found in myeloid malignancies

被引：21

作者：

Wong, Jasmine C. Y. ^{[2
]}

Zhang, Yan ^{[1
]}

Lieuw, Kenneth H. ^{[3
]}

Tran, Mary T. ^{[2
]}

Forgo, Erna ^{[2
]}

Weinfurtner, Kelley ^{[2
]}

Alzamora, Pilar ^{[2
]}

Kogan, Scott C. ^{[4
]}

Akagi, Keiko ^{[5
]}

Wolff, Linda ^{[6
]}

Le Beau, Michelle M. ^{[7
,8
]}

Killeen, Nigel ^{[1
]}

Shannon, Kevin ^{[2
]}

机构：

[1] Univ Calif San Francisco, Dept Microbiol & Immunol, San Francisco, CA 94143 USA

[2] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA

[3] Uniformed Univ Hlth Sci, Dept Pediat, Bethesda, MD USA

[4] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA

[5] Ohio State Univ, Dept Mol Virol Immunol & Med Genet, Ctr Comprehens Canc, Columbus, OH 43210 USA

[6] NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA

[7] Univ Chicago, Hematol Oncol Sect, Chicago, IL 60637 USA

[8] Univ Chicago, Canc Res Ctr, Chicago, IL 60637 USA

来源：

BLOOD | 2010年 / 115卷 / 22期

基金：

美国国家卫生研究院;

关键词：

THERAPY-RELATED MYELODYSPLASIA; LONG-ARM DELETIONS; TUMOR-SUPPRESSOR; MYELOPROLIFERATIVE DISORDER; HEMATOPOIETIC-CELLS; CHILDHOOD MONOSOMY-7; CRE RECOMBINASE; CANDIDATE GENE; LEUKEMIA; MUTATIONS;

D O I：

10.1182/blood-2009-07-232504

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Monosomy 7 and del(7q) are associated with adverse features in myeloid malignancies. A 2.5-Mb commonly deleted segment (CDS) of chromosome band 7q22 is implicated as harboring a myeloid tumor suppressor gene (TSG); however, molecular analysis of candidate TSGs has not uncovered loss of function. To determine whether haploinsufficiency for the 7q22 CDS contributes to myeloid leukemogenesis, we performed sequential gene targeting to flank a region of orthologous synteny on mouse chromosome band 5A3 with loxP sites. We then generated Mx1-Cre, 5A3(fl) mutant mice and deleted the targeted interval in vivo. Although excision was inefficient, we confirmed somatic deletion of the 5A3 CDS in the hematopoietic stem cell compartment. Mx1-Cre, 5A3(fl) mice show normal hematologic parameters and do not spontaneously develop myeloid malignancies. The 5A3(fl) deletion does not cooperate with oncogenic Kras(G12D) expression, Nf1 inactivation, or retroviral mutagenesis to accelerate leukemia development and did not modulate responsiveness to antileukemia drugs. These studies demonstrate that it is feasible to somatically delete a large chromosomal segment implicated in tumor suppression in hematopoietic cell populations in vivo; however, our data do not support the hypothesis that the 7q22/5A3 CDS interval contains a myeloid TSG. (Blood. 2010; 115(22): 4524-4532)

引用

页码：4524 / 4532

页数：9