# Characterization of NUP205 as a haploinsufficient essential gene for the treatment of  hematopoietic malignancies

> **NIH NIH R37** · OREGON HEALTH & SCIENCE UNIVERSITY · 2024 · $378,405

## Abstract

PROJECT SUMMARY/ABSTRACT
Complete or partial loss of chromosome 7 (-7/del(7q))
predisposition syndromes, preleukemia, and leukemia.
is the most common cytogenetic abnormality in
It is associated with short overall survival and
chemotherapy resistance. Given their high prevalence and unfavorable prognosis, there is an urgent need to
identify more effective and innovative therapies. Nonetheless, the pathogenesis and therapeutic vulnerabilities
of -7/del(7q) remain undetermined.
 We hypothesize that the hemizygous deletion of one or more haploinsufficient essential genes on
chromosome 7q is responsible for ineffective hematopoiesis, akin to the partial loss of ribosomal proteins in 5q
deletion myelodysplastic syndrome (MDS) and inherited BM failure syndromes. Such a hemizygous deletion
may create specific vulnerabilities that could be therapeutically targeted by further inhibiting the encoded protein,
a related protein, or an associated pathway.
 Nuclear pore complexes (NPCs) play a crucial role in regulating several vital cellular processes by
controlling the nuclear-cytoplasmic trafficking of RNA, ribosomes, transcription regulators, and drug targets. We
conducted comprehensive statistical analyses and individual CRISPR knockout experiments, which revealed
NUP205, an NPC member, to be a haploinsufficient essential gene on chromosome 7q. Knockout or knockdown
of NUP205 results in a growth disadvantage or cell apoptosis in a dose-dependent manner. NUP205 hemizygous
deletion single-cell clones exhibit resistance to cytarabine and increased sensitivity to elesclomol, consistent with
the drug profile of -7/del(7q) primary leukemia samples in the Beat AML cohort. Therefore, we hypothesize that
the deletion of the haploinsufficient essential gene NUP205 contributes to the BM insufficiency phenotype
observed in -7/del(7q) patients and can be therapeutically targeted using elesclomol-based treatments to
specifically eliminate malignant cells harboring -7/del(7q).
 We propose here: (1) to investigate the functional impacts of NUP205 on hematopoiesis; (2) to elucidate
the mechanisms of NUP205 deletion-mediated impacts on cellular activity and chemosensitivity; (3) to
investigate elesclomol combination therapies targeting leukemia cells harboring -7/del(7q).
 Collectively, our studies will elucidate the cellular and molecular mechanisms of NUP205 deletions in driving
the BM insufficiency phenotype, creating specific vulnerabilities, and shaping the drug responses for subsets of
myeloid malignancies. Ultimately, this effort will provide a basis for further translational work and the
development of promising inhibitors for clinical testing. Additionally, our study will serve as a prototype for
identifying novel therapeutic vulnerabilities for other chromosome deletions in hematological malignancies.

## Key facts

- **NIH application ID:** 10860710
- **Project number:** 1R37CA284012-01A1
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Haijiao Zhang
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $378,405
- **Award type:** 1
- **Project period:** 2024-05-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10860710

## Citation

> US National Institutes of Health, RePORTER application 10860710, Characterization of NUP205 as a haploinsufficient essential gene for the treatment of  hematopoietic malignancies (1R37CA284012-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10860710. Licensed CC0.

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