# In Vivo Functional Analysis of Chromosome 7q22 Deletions in Myeloid Malignancies

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $338,672

## Abstract

ABSTRACT
Recurring losses of large chromosomal regions are a hallmark of pediatric and adult cancer genomes that
pose exceptional challenges for uncovering how these deletions contribute to malignant growth. Monosomy 7
(-7) and del(7q) (-7/del(7q)) are recurring cytogenetic abnormalities in de novo myeloid malignancies that are
strongly associated with cases of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) arising
in children and in adolescent/young adult (AYA) patients with inherited cancer predispositions and in those who
develop myeloid malignancies after treatment for a primary cancer. Therapy-induced MDS and AML (t-MDS
and t-AML) are particularly relevant to the pediatric and AYA population due to modern intensive treatment
protocols for many solid cancers, which are frequently curative. As a result, there is a large and growing
population of “at risk” pediatric and AYA cancer survivors. Unfortunately, t-MDS/t-AML and other myeloid
malignancies with chromosome 7 deletions are highly refractory to current therapies. Extensive cytogenetic
and genome wide analysis studies implicate deletions of chromosome band 7q22 in leukemogenesis; however,
sequencing studies and transcriptome analysis did not reveal frequent homozygous inactivation of any
candidate 7q tumor suppressor gene in myeloid malignancies. These data implicate haploinsufficiency for one
or more 7q genes in leukemogenesis, which pose formidable challenges for elucidating the underlying
molecular mechanisms. To address this fundamental problem, we deployed chromosome engineering to
create 5A3+/del and 5G2+/del mice, which respectively harbor deletions in mouse chromosome bands 5A3 and
5G2. These deletions span ~4 MB of genomic DNA that is syntenic to the most common 7q22 deletions
identified in human patients. 5A3+/del hematopoietic stem and progenitor cells (HSPC) exhibit “preleukemic”
abnormalities, but these mice do not spontaneously develop MDS or AML. Preliminary studies of 5G2+/del mice
also revealed HSPC abnormalities and exposing this strain to N-ethyl-N-nitrosourea (ENU) accelerated the
development of hematologic cancer. We will utilize these novel models of 7q22 deletions to pursue the
following specific aims: (1) to functionally interrogate hematopoiesis in 5G2+/del and 5A3+/del/5G2+/del mice and to
observe cohorts of mice for the development of myeloid malignancies; (2) to investigate the effects of DNA
damaging agents on 5A3+/del/5G2+/del HSPC; and, (3) to model the complex genetics of myeloid malignancies
with -7/del(7q) by introducing cooperating mutations into 5A3+/del/5G2+/del HSPC and assessing the phenotypic
and functional consequences in vivo. Genetically engineered mice that accurately model recurrent
chromosome band 7q22 deletions found in human myeloid malignancies are a versatile system for performing
functional studies and testing new therapeutic strategies.

## Key facts

- **NIH application ID:** 9924474
- **Project number:** 5R01CA216352-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** KEVIN M. SHANNON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $338,672
- **Award type:** 5
- **Project period:** 2017-05-22 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9924474

## Citation

> US National Institutes of Health, RePORTER application 9924474, In Vivo Functional Analysis of Chromosome 7q22 Deletions in Myeloid Malignancies (5R01CA216352-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9924474. Licensed CC0.

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