Use of chromosome engineering to model a segmental deletion of chromosome band 7q22 found in myeloid malignancies.
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.
Wong
Jasmine C Y
JC
Department of Pediatrics, University of California, San Francisco, CA 94143, USA.
Zhang
Yan
Y
Lieuw
Kenneth H
KH
Tran
Mary T
MT
Forgo
Erna
E
Weinfurtner
Kelley
K
Alzamora
Pilar
P
Kogan
Scott C
SC
Akagi
Keiko
K
Wolff
Linda
L
Le Beau
Michelle M
MM
Killeen
Nigel
N
Shannon
Kevin
K
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001483:Base Sequence; D002871:Chromosome Banding; D002872:Chromosome Deletion; D002874:Chromosome Mapping; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics*; D017931:DNA Primers / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D018390:Gene Targeting; D016514:Genes, Neurofibromatosis 1; D016147:Genes, Tumor Suppressor; D005818:Genetic Engineering / Q000379:methods; D006801:Humans; D007942:Leukemia, Experimental / Q000188:drug therapy / Q000235:genetics*; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008957:Models, Genetic; D016254:Mutagenesis, Insertional; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D011995:Recombination, Genetic; D013045:Species Specificity
D000970:Antineoplastic Agents; D017931:DNA Primers; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)