# The pathogenesis of chromosome 7q deletions in juvenile myelomonocytic leukemia

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2020 · $365,129

## Abstract

Pediatric malignancies frequently harbor chromosome-arm level copy number changes that potentially impact
the expression level of a large number of genes, yet how segmental alterations contribute to tumorigenesis
remains poorly defined. This is a major gap in our understanding of the pathogenesis of childhood cancers
and hampers the rational design of new therapies. One such deletion is loss of part or all of chromosome 7
[-7/del(7q)], the most common cytogenetic abnormality in myeloid malignancies of childhood. -7/del(7q) occurs
in up to 33% of juvenile myelomonocytic leukemias (JMML), which are aggressive myelodysplastic
syndrome/myeloproliferative neoplasms (MDS/MPN) characterized by RAS pathway mutations and few other
somatic alterations. In myeloid malignancies, -7/del(7q) is associated with treatment resistance and a poor
prognosis for reasons that are not understood. The long-term goal of this proposal is to understand the
molecular pathogenesis of -7/del(7q) and to reveal new therapeutic targets for JMML patients. In previous
work, we reported that the transcription factor, CUX1, is a highly conserved myeloid tumor suppressor gene
encoded on 7q. We demonstrated a striking association of oncogenic RAS pathway mutations with CUX1
deletions across tumor types. We recently engineered a Cux1 knockdown mouse model (Cux1low), which
develops a spontaneous MDS/MPN with features of human JMML, including myelomonocytic expansion in all
hematopoietic compartments with infiltration into non-hematopoietic tissues, dysplasia in all myeloid lineages,
and anemia. In addition to CUX1, 7q deletions are typically large and span other established or putative tumor
suppressor genes and/or myeloid regulators. In this proposal, we will test the hypothesis that 7q is a
`Contiguous gene syndrome' region, wherein combined dosage imbalance of multiple genes drives JMML, in
combination with oncogenic RAS signaling. We will use our unique mouse model and CRISPR/Cas9 genome
editing to achieve the following Specific Aims: 1) Identify the cellular and molecular mechanisms by which
Cux1 knockdown and Ras cooperate in JMML; 2) Define the pathogenesis of combinatorial dosage imbalance
of 7q genes in JMML. This work will have a positive impact on the field of myeloid malignancies by: i)
elucidating the molecular mechanisms by which combinatorial loss of 7q genes drives disease; ii) identifying
new molecular targets for the treatment of JMML; and iii) establishing a physiologically accurate mouse model
in which novel therapies for human disease can be rapidly tested and optimized. Our mouse model of JMML
will fulfill a major unmet need for childhood myeloid malignancies, specifically a preclinical mouse model for
screening of approved and experimental drugs in future studies. Our work will reveal the relevant proliferative
and differentiation pathways for therapeutic targets to test in this model.

## Key facts

- **NIH application ID:** 9991788
- **Project number:** 5R01CA231880-03
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Megan McNerney
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $365,129
- **Award type:** 5
- **Project period:** 2018-09-20 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9991788

## Citation

> US National Institutes of Health, RePORTER application 9991788, The pathogenesis of chromosome 7q deletions in juvenile myelomonocytic leukemia (5R01CA231880-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9991788. Licensed CC0.

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