Systematic Study Explores ALK-Negative Anaplastic Large Cell Lymphoma Patients’ Genomes

Systematic Study Explores ALK-Negative Anaplastic Large Cell Lymphoma Patients’ Genomes

A team of researchers from Columbia University Medical Center (CUMC) and the Weill Cornell Medical College recently published the first-ever systematic study of the genomes of patients with ALK-negative anaplastic large cell lymphoma (ALCL), an aggressive type of non-Hodgkin’s lymphoma (NHL). Results from the study published in the journal Cancer Cell revealed that, in some patients, the condition is driven by changes in the JAK/STAT3 cell signaling pathway. The researchers also found that a compound can inhibit this pathway in mice models of ALCL tumors, offering potential effective treatments for the disease.

“Current therapies for this form of lymphoma fail to work in the majority of cases. However, now that we know the mutations that drive a significant percentage of cases, we can envision a new, personalized genomic approach to the treatment of ALK-negative ALCL,” said co-study leader Raul Rabadan, PhD, associate professor of systems biology and of biomedical informatics at Columbia University in a recent news release.

Every year there are approximately 70,000 new diagnosed cases of NHL with about 3% corresponding to ALCL. Patients with a diagnosis of systemic ALCL can be categorized in two different groups, depending on the abnormal expression of a protein named anaplastic lymphoma kinase (ALK). Lymphomas that are ALK-positive usually respond to chemotherapy treatment, with 70% of patients having a long-term survival rate free of the disease.

In the study, Dr. Rabadan and his co-workers analyzed a total of 155 patients with ALCL and 74 controls (patients with other forms of lymphoma), performing exome sequencing of tumor cells. The results revealed that 20% of patients with ALK-negative ALCL had genetic mutations in the JAK1 gene or in the STAT3 gene. Of these, 38% had mutations in both genes.

The team uncovered that mutations in these two genes are responsible for an abnormal activation of the JAK/STAT3 signaling pathway, a pathway responsible for transmitting chemical signals from outside the cell to genes in the cell nucleus. Various forms of cancer have been found to have an overactivation of this pathway.

The results also revealed that the presence of novel gene fusions was responsible for the activation of the JAK/STAT3 pathway, and that patients who had these specific fusions did not carry mutations in the JAK1 or STAT3 genes, indicating the cause of ALK-negative ALCL is independent of such fusions.

The team used inhibitors of the JAK/STAT3 pathway in mice models of ALK-negative ALCL, observing these could inhibit tumour growth when compared to controls.

“Our findings demonstrate that drugs targeting the JAK/STAT3 pathway offer a viable therapeutic strategy in a subset of patients with ALCL,” said Dr. Rabadan in the news release. “A couple of JAK/STAT3 inhibitors have been approved by the FDA for the treatment of psoriasis and rheumatoid arthritis, and several more are currently in clinical trials. These could be tested in patients whose genetic profile matches those we identified in our study.”

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Daniela holds a PhD in Clinical Psychology from The University of Edinburgh, United Kingdom, a MSc in Health Psychology and a BSc in Clinical Psychology. Her work has been focused on vulnerability to psychopathology and early identification and intervention in psychosis.

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