# Protein Phosphatase PP2A and DNA damage in cell fate decisions of acute myeloid leukemic cells

> **NIH NIH F99** · OHIO STATE UNIVERSITY · 2020 · $38,019

## Abstract

PROJECT SUMMARY
Acute Myeloid Leukemia (AML) is a cancer characterized by a co-operative block in hematopoietic maturation
and proliferative advantage. It is near incurable, with a 5-year survival rate of only 25% and median survival
<1year in patients over 65 years. Current chemotherapy is very poorly tolerated and majority of patients relapse.
Overcoming the differentiation block is a promising therapeutic avenue, however is majorly lacking for AML
subtypes without a known driver oncogene. Our study examines new pathways to target the two major aspects
of leukemic cell survival, the differentiation block and increased proliferative ability, that can prove effective
across multiple subtypes.
Reversible protein phosphorylation controls many aspects of such cell fate decisions, and an imbalance in the
normal activities of kinases and phosphatases contribute to pathogenesis of AML. However, while the aberrant
activation of kinases, frequent in AML, is well studied and exploited for therapeutic purposes, inactivation of
phosphatases, also prevalent in AML, is often overlooked. This proposal focuses on the serine threonine
phosphatase tumor suppressor Protein Phosphatase 2A (PP2A) and its role in influencing proliferation vs
differentiation decisions in AML. For the F99 phase, we identified a novel role for PP2A in driving myeloid
differentiation and cell cycle arrest in AML. Based on our preliminary data, our overall hypothesis is that PP2A
drives differentiation and cell cycle arrest through the cell cycle regulator p21. We specifically seek to establish
the mechanism of PP2A mediated p21 induction, and the role of potential downstream factors Retinoblastoma
protein and CEBP proteins in driving differentiation in AML using genetic overexpression and knockdown
systems, CHIP-Seq and single cell analysis using Mass Cytometry.
The K00 phase focuses on identification of factors mediating DNA damage induced differentiation. While DNA
damage has been shown to induce differentiation in AML and hematopoietic progenitors, the molecular
mechanism is poorly understood. Interestingly, DNA repair machinery including ATM and ATR serine threonine
kinases protect leukemic cells from damage induced differentiation and are hyperactivated in AML. This raises
the possibility that inhibiting DNA repair can promote genomic stress induced differentiation. My hypothesis for
the K00 phase is that PP2A can antagonize DNA repair kinases and promote differentiation in response to DNA
damage in AML. I will establish the role of PP2A and other potential candidates identified from preliminary data
and literature such as GADD45 proteins and p21 in DNA damage induced differentiation in AML using genetic
and pharmacological activation of PP2A, overexpression, knockdown and knockout of GADD45 as well as global
in-vitro and in-vivo RNAi and genome wide CRISPER screen analyses. Successful completion of this proposal
will yield new insight into cellular pathways capable of inducing grow...

## Key facts

- **NIH application ID:** 10019487
- **Project number:** 5F99CA245813-02
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Swagata Goswami
- **Activity code:** F99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $38,019
- **Award type:** 5
- **Project period:** 2019-09-17 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10019487

## Citation

> US National Institutes of Health, RePORTER application 10019487, Protein Phosphatase PP2A and DNA damage in cell fate decisions of acute myeloid leukemic cells (5F99CA245813-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10019487. Licensed CC0.

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