Prognosis for patients with splenic marginal zone lymphoma (SMZL)
Lymphomas are a heterogeneous group of hematological malignancies that accounts for ~5% of all cancers worldwide. Due to their heterogeneity, lymphomas vary significantly in their severity, from indolent to very aggressive forms. Thus, accurate diagnosis and prediction of disease progression is very important in determining the best treatment course for each patient. Splenic marginal zone lymphoma (SMZL) is a B-cell lymphoma that is the most common primary lymphoma of the spleen, and it accounts for ~2% of all lymphoid malignancies. Although in most patients it is an indolent condition that has a good prognosis, a subset of patients present a more aggressive form of the disease that can undergo transformation to higher-grade diseases such as diffuse large B-cell lymphoma (DLBCL). Currently prognosis for SMZL is based on levels of hemoglobin, lactate dehydrogenase, and albumin found in patient’s serum. Very little is known about the genetic events that lead to the development of aggressive disease, and having this information will enable better accuracy of prognosis, timing of therapy initiation as well as choice of therapy.
Mutations in NOTCH2 gene correlate with poor SMZL prognosis
Researchers in the Department of Pathology at the University of Michigan discovered that mutations in NOTCH2 gene correlate with poor prognosis for patients with SMZL. NOTCH receptors are a heterodimeric transmembrane proteins that regulate a variety of cellular processes by downstream activation of gene transcription. Upon ligand binding, the active intracellular domain of NOTCH receptor is cleaved and translocated to the nucleus. Researchers found that in patients with aggressive SMZL, NOTCH2 harbors somatic mutations that cause it to be truncated, leading to hyperactivation of NOTCH2 signaling. Additionally, these truncated proteins lack a ubiquitination signal, leading to enhanced NOTCH2 stability. These NOTCH2 mutations are specific for SMZL as other lymphomas and leukemias all had a wild-type gene. Mutations in NOTCH2 can thus be used as a biomarker for SMZL disease prognosis, selection of therapy, and NOTCH2-targeted therapy could be explored as a SMZL therapeutic.
Applications and Advantages
- Molecular diagnostic biomarker for lymphoma
- Differential diagnosis and prognosis for SMZL
- Target for SMZL therapeutic
- First genetic test for SMZL diagnosis and prognosis
- Can detect aggressive SMZL without clinical symptoms
- Improve outcomes for patients with aggressive SMZL