# Molecular Classification of Anaplastic Large Cell Lymphoma

> **NIH NIH P01** · MAYO CLINIC ARIZONA · 2021 · $594,813

## Abstract

T-cell lymphomas represent a heterogeneous and understudied group of malignancies of the immune system
with poor response to standard therapy in most cases. However, subsets of patients have excellent outcomes
for unknown reasons. The goal of this project is to develop personalized medicine strategies for patients with
anaplastic large cell lymphoma (ALCL), one of the most common types of T-cell lymphoma. Specifically, we
will use genomic discovery to develop genetic tests that: (1) identify specific drug targets in tumor tissue and
guide targeted therapy, and (2) distinguish highly aggressive tumors from less aggressive so that the intensity
of therapy can be individualized. Currently, only one gene, ALK, is tested to classify ALCLs. Our team has
identified chromosome abnormalities of two other genes in ALCL, DUSP22 and TP63. Five-year survival rates
for ALCL patients with abnormal DUSP22 are 90%, compared to only 17% for patients with abnormal TP63.
The reasons for this marked difference in survival remain unknown, and both groups of patients currently
receive the same treatment. Furthermore, some ALCLs grow in response to a group of growth-promoting
proteins collectively known as JAK-STAT3. Importantly, tumor growth caused by JAK-STAT3 can be blocked
by drugs that target these proteins. However, the relationship between JAK-STAT3 proteins and DUSP22 and
TP63 abnormalities has not been studied. In Aim 1, we will determine the relationship of DUSP22- and TP63-
rearranged ALCLs to dysregulation of the JAK-STAT3 pathway using a combination of RNA sequencing to
examine gene expression and mass spectrometry to assess protein activation. We anticipate developing
laboratory tests that differentiate these distinct types of ALCL, and also identifying key growth-promoting
proteins that could lead to new targeted therapies for ALCLs that lack JAK-STAT. In Aim 2, we will identify the
spectrum and role of mutations in ALCL. Specifically, we have discovered mutations that alter proteins called
basic helix-loop-helix (bHLH) transcription factors that are key regulators of gene expression in lymphocytes.
We anticipate that bHLH gene mutations will cooperate with other abnormalities (e.g., DUSP22) to promote
tumor growth, and that understanding this cooperation will lead to new therapies for ALCLs. In Aim 3, we will
characterize the methylome of DUSP22-rearranged and other ALCLs to identify key differences in DNA
methylation, a major factor controlling the specific genes that are expressed in a given cell. Our data suggest
that ALCLs vary widely in their degree of DNA methylation. We anticipate finding that the methylation pattern in
ALCLs with DUSP22 abnormalities leads to expression of proteins known as cancer-testis antigens,
suggesting that these tumors may be particularly sensitive to therapies that enhance antitumor responses of
the host immune system. In contrast, we anticipate that ALCLs with excessive methylation will respond to
drugs designed to reduc...

## Key facts

- **NIH application ID:** 10237160
- **Project number:** 5P01CA229100-04
- **Recipient organization:** MAYO CLINIC ARIZONA
- **Principal Investigator:** Andrew Lewis Feldman
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $594,813
- **Award type:** 5
- **Project period:** 2018-09-19 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10237160

## Citation

> US National Institutes of Health, RePORTER application 10237160, Molecular Classification of Anaplastic Large Cell Lymphoma (5P01CA229100-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10237160. Licensed CC0.

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