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Updated: Jun 15, 2026
Chromosome Preparation From Cultured Cells
Published on: January 28, 2014
Use of chromosome engineering to model a segmental deletion of chromosome band 7q22 found in myeloid malignancies
Jasmine C Y Wong1, Yan Zhang, Kenneth H Lieuw
1Department of Pediatrics, University of California, San Francisco, CA 94143, USA.
Abstract:
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.
Insights
Monosomy 7 and del(7q) deletions in myeloid malignancies are linked to poor outcomes. This study found that deleting a large segment on mouse chromosome 5A3 did not cause leukemia, suggesting it lacks a myeloid tumor suppressor gene.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- Monosomy 7 and del(7q) are associated with adverse outcomes in myeloid malignancies.
- A commonly deleted segment (CDS) at chromosome 7q22 is suspected to harbor a myeloid tumor suppressor gene (TSG).
- Previous molecular analyses have not identified a TSG within this region with loss of function.
Purpose of the Study:
- To investigate if haploinsufficiency of the 7q22 CDS contributes to myeloid leukemogenesis.
- To determine if the 7q22/5A3 CDS interval contains a myeloid TSG.
Main Methods:
- Generated Mx1-Cre, 5A3(fl) mutant mice to allow somatic deletion of a targeted interval in mouse chromosome band 5A3, orthologous to human 7q22.
- Confirmed somatic deletion of the 5A3 CDS in the hematopoietic stem cell compartment.
- Assessed the impact of 5A3(fl) deletion on leukemogenesis, alone and in combination with oncogenic mutations or mutagenesis, and evaluated drug responsiveness.
Main Results:
- Somatic deletion of the 5A3 CDS in hematopoietic stem cells was confirmed, although excision was inefficient.
- Mx1-Cre, 5A3(fl) mice exhibited normal hematologic parameters and did not develop spontaneous myeloid malignancies.
- Deletion of the 5A3(fl) interval did not accelerate leukemia development when combined with Kras(G12D) expression, Nf1 inactivation, or retroviral mutagenesis.
- The deletion did not alter responsiveness to antileukemia drugs.
Conclusions:
- It is feasible to somatically delete large chromosomal segments implicated in tumor suppression within hematopoietic cells in vivo.
- The 7q22/5A3 CDS interval does not appear to contain a myeloid tumor suppressor gene, as haploinsufficiency did not lead to myeloid leukemogenesis in mice.
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