# Targeting the p62 signalosome in leukemia.

> **NIH NIH R01** · UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA · 2020 · $335,119

## Abstract

Project Summary/Abstract
Patients with certain subtypes of leukemia are associated with dismal outcomes due to resistance to current
treatment options, particularly for those with MLL rearrangements. Chronic NF-B activity is observed in
leukemia cells, especially within the leukemia stem cell (LSC) population, and is implicated as a requirement for
leukemogenesis, including the MLL-driven leukemia. Given the pleotropic function of NF-B, targeting the
leukemia-specific function of NF-B is urgently needed. However, the molecular mechanism of the leukemia-
specific function of NF-B is unclear. Previous studies implicate the adaptor protein Sequestosome 1 (also known
as p62) as dispensable for normal hematopoietic stem and progenitor cell (HSPC) function. Intriguingly we find
that p62 is overexpressed in leukemia cells, and associated with increased TNF in leukemia patients. p62 was
shown to form a signalosome with RIPK1 (p62/RIPK1) via its ZZ domain in response to TNF, leading to NF-B
activation. Our functional study reveals that p62 is required for leukemia cell function through activating NF-B,
indicating HSPC acquire a dependency on p62 function during transformation and p62-mediated signaling
pathway represents a leukemia-specific mechanism that activates NF-B. My long-term goal is to improve the
targeted therapy by identifying leukemia-specific signaling pathways and testing novel therapeutic approaches.
The objectives of this proposal are to: (1) determine the contribution of p62 to promoting leukemia; (2) elucidate
the molecular mechanism of p62 in activating NF-B in leukemia; and (3) test targeting the leukemia-specific
p62 signalosome with a small molecule compound as a means to inactive NF-B and inhibit leukemia cell and
LSC while preserving normal HSPC. We hypothesize that p62 promotes leukemia by forming a leukemia-
specific p62/RIPK1 signalosome that activates NF-B. In particular, given that p62 supports MLL leukemia cell
growth and NF-B mediates MLL-driven leukemogenesis, we will determine the contribution of p62 in promoting
MLL leukemia by examining preleukemia and leukemia phenotype in Mll-AF9 knockin mice followed by p62
deletion (Mll-AF9+/-;p62mice). We will determine whether p62 promotes leukemia through activating NF-B.
In addition, we will determine whether p62 binds RIPK1 in leukemia cells, and whether the p62/RIPK1
signalosome is essential for NF-B activation and leukemogenesis. Moreover, we will examine whether the ZZ
domain on p62 is required for forming the p62/RIP signalosome, activating NF-B and promoting leukemia.
Finally, we will test a small molecule compound that specifically targets the p62 ZZ domain in disrupting the
p62/RIPK1 signalosome, inactivating NF-B and inhibiting leukemia cells and LSC while preserving normal
HSPC. We anticipate that targeting the leukemia-specific p62 signalosome exerts antileukemia effect without
damaging normal cells. The proposed study will impact on our understand...

## Key facts

- **NIH application ID:** 9987329
- **Project number:** 5R01CA218076-04
- **Recipient organization:** UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
- **Principal Investigator:** Jing Fang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $335,119
- **Award type:** 5
- **Project period:** 2019-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9987329

## Citation

> US National Institutes of Health, RePORTER application 9987329, Targeting the p62 signalosome in leukemia. (5R01CA218076-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9987329. Licensed CC0.

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