Project Term
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Project Summary
Patients with B cell malignancies who do not fall into a distinct pathological disease category pose a challenge for patient care, and patient classification has been exacerbated by the recent emergence of two separate classification systems. Genome-wide DNA methylation is a stable and information-rich biomarker that has been successfully used to classify other cancer types, however remains understudied in hairy cell leukemia and related splenic B cell lymphoma and leukemia. In this proposal we will investigate the utility of DNA methylation to establish a novel, unbiased, biologically-based classification paradigm for hairy cell leukemia, with a focus on the variant subtype, and investigate novel mechanisms and etiology underlying these rare leukemia patients.
Lay Abstract
Some patients with blood cancers cannot be clearly diagnosed because their disease looks very similar to other types using current medical tests. This is a serious problem since proper treatment depends on knowing the exact cancer type. One example is hairy cell leukemia variant (HCL-V), which is often hard to tell apart from other rare cancers of the spleen and blood.
DNA methylation–tiny chemical changes to DNA that control how genes work–remains stable and carries a wealth of information; yet, its use in these rare cancers has not been well studied. In the largest study of its kind to date, we analyzed DNA methylation in 383 patients with these uncommon blood cancers. The results reorganized them into six unique groups, each with its own biological and clinical features. This suggests that using DNA methylation may allow us to classify these cancers in a new, unbiased way, improving diagnosis and deepening our understanding of these rare diseases.
Our proposal has three Specific Aims:
Aim 1: Study new biological features of HCL-V subtypes. We have already discovered four distinct subtypes with unique genetic events, including rearrangements in a cancer-driving gene (TCL1A), mutations affecting telomere control (TERT, POT1), and other important changes. We will study how these genetic events drive disease.
Aim 2: Build and test a DNA methylation–based diagnostic tool. We will create a classifier that groups patients based on DNA methylation and test it in a separate group of well-studied patients. We will compare its accuracy against current diagnostic methods and use it to assess the relationship between DNA methylation and clinical outcomes.
Aim 3: Translate this approach into patient-friendly tools. Currently, spleen tissue is often needed for a final diagnosis, which requires invasive and/or risky tests. Our research shows that DNA methylation patterns are similar in both blood and spleen samples. This means we may be able to create a safer, non-invasive test that uses blood to mimic (“virtually” replace) spleen tissue analysis.
Impact:
This project could revolutionize how these rare blood cancers are diagnosed. By replacing invasive procedures with blood-based tests and improving accuracy, we aim to give patients faster, safer, and more precise answers—leading to better care and new biological insights.
The Hairy Cell Leukemia Foundation (HCLF) and Blood Cancer United have joined forces to create the Hairy Cell Leukemia Research Initiative program to support targeted research to build a more comprehensive foundational understanding of the molecular basis of hairy cell leukemia (HCL), develop additional therapies, and optimize outcomes for patients with this disease.
Program
