# Delineating the role of calcineurin in modulating the immune response in acute lymphoblastic leukemia

> **NIH NIH F31** · EMORY UNIVERSITY · 2021 · $46,036

## Abstract

Project Summary
Leukemia is the most common cancer in children, and although prognosis has improved over the last several
decades, the mortality rate is still 15-20% in children diagnosed with acute lymphoblastic leukemia (ALL).
Consequently, leukemia is a leading cause of disease-related deaths in children. Although new therapies
have shown the potency of the immune system for leukemia elimination, much is still unknown regarding
immune escape mechanisms in leukemia. Previous studies have implicated calcineurin (Cn), a serine
threonine phosphatase, in the promotion of leukemogenesis in T-ALL, yet its role in B cell-ALL (B-ALL) has
not been well established. Our lab discovered extended survival in immune-competent mice engrafted with
leukemia in which the essential regulatory subunit, CnB was knocked down. Yet, survival was not as
prolonged in Rag1-/- mice (lacking mature B and T cells; thus, no adaptive immunity) engrafted with
calcineurin-deficient leukemia (shCnB). These data implicate Cn as an important mediator of immune
evasion during leukemia progression. To identify downstream effectors of Cn-dependent immune evasion,
we defined the cytokine profiles from control leukemia (shNS) and shCnB cells and found that IL-12 secretion
in shCnB leukemia was significantly increased compared to shNS leukemia. IL-12 is an interleukin produced
by antigen-presenting cells that induces interferon-gamma (IFN-γ) production by both T and natural killer
(NK) cells, resulting in cytolytic killing of cancer cells and other pathogens. To further explore this finding, WT
and Rag1-/- mice were engrafted with B-ALL and administered recombinant IL-12 (rIL-12). Both WT and
Rag1-/- exhibited a prolonged survival with rIL-12 administration. This points to a clear role of the innate
immune system in immune surveillance of leukemia. NK cells have a major role in innate immunity thus I
intend to test the hypothesis that IL-12 secretion is regulated by Cn in B-ALL cells and also potently activates
NK cells resulting in leukemia clearance. In Aim 1, we will determine how Cn regulates IL-12 secretion in B-
ALL cells by using pharmacologic and genetic methods to inhibit Cn to explore IL-12 secretion and also its
downstream target NFAT in both human and murine B-ALL cells and also primary B-ALL patient samples.
In Aim 2, we will define the contributions of NK cells to anti-leukemia immunity using models of NK deficiency
and complementation assays. NK cell activation in response to shNS and shCnB leukemia cells will also be
examined using cytotoxicity assays. Our goal is to better understand immune evasion in hematological
malignancies to develop novel immunotherapies to control leukemia.

## Key facts

- **NIH application ID:** 10118006
- **Project number:** 5F31CA243472-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Alisha Desiree Hunter
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $46,036
- **Award type:** 5
- **Project period:** 2020-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10118006

## Citation

> US National Institutes of Health, RePORTER application 10118006, Delineating the role of calcineurin in modulating the immune response in acute lymphoblastic leukemia (5F31CA243472-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10118006. Licensed CC0.

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