Bing Center Discovers Highly Prevalent Mutations in the CXCR4 gene in Patients with Waldenstrom’s Macroglobulinemia
Scientists from the Bing Center for WM published two highly impactful articles in the journal BLOOD, including a Plenary Contribution led by Zachary Hunter and an Original Contribution led by Steve Treon that describe the identification of highly prevalent mutations in the CXCR4 gene. Mutations found in the CXCR4 gene represent the second most common mutations after MYD88 L265P that was previously reported by the Bing Center in the New England Journal of Medicine in 2012 in over 90% of patients with WM.
CXCR4 is a receptor (cell surface protein) that binds to stromal derived factor 1a (SDF-1a) that is released by bone marrow cells. Binding of SDF-1a to CXCR4 triggers WM cells to home in on the bone marrow where they take residence and find additional growth and survival factors that allow their expansion. In these published studies, Bing Center researchers identified mutations in the C-terminal domain of CXCR4 of malignant cells isolated from bone marrow biopsies from 30% of WM patients. The C-terminal domain is a critical area for regulatory function of CXCR4, and mutations in this region activate signaling. The mutations are similar to those found in patients with WHIM syndrome, a congenital condition that is associated with increased trafficking of white blood cells from the blood to the bone marrow thereby making patients vulnerable to infections. In contrast to WHIM patients who have mutations in CXCR4 in all their cells, patients with WM only have the WHIM mutations in their WM cells. The Bing Center investigators have discovered over 30 different types of mutations in the C-terminal domain which include non-sense and frameshift mutations. Non-sense mutations result in a truncation of the protein which deprives negative regulatory proteins from binding to the C-terminal domain to shutoff SDF-1a triggered signaling. Frameshift mutations occur when mutations result in scrambling of the genetic code used to make up the C-terminal domain. Frameshift mutations occur when either extra nucleotides are inserted into the gene, or deletions occur taking away nucleotides. Approximately half of WM patients have non-sense mutations the most common of which is S338X mutation that occurs at amino acid position 338, while the other half of patients have frameshift mutations.
Mutations in CXCR4 are the first to be described for any cancer in WM patients. The presence and type of CXCR4 mutation impacts disease presentation in WM patients. Patients who have CXCR4 non-sense mutations tend to present with more aggressive disease including greater bone marrow involvement, serum IgM secretion, and symptomatic disease including hyperviscosity crisis at presentation. The functional relevance of non-sense mutations was recently addressed by Dr. Yang Cao from the Bing Center who presented a poster at the American Society of Hematology in 2012, and then in 2013 modeling the impact of the S338X CXCR4 non-sense mutation in WM cells. Using a lentiviral transfection system to place the mutated gene in WM cells, she showed that the S338X mutation caused cells to show enhanced survival in the presence of ibrutinib, an inhibitor of Bruton’s Tyrosine Kinase. Enhanced survival and resistance to ibrutinib accompanied increased phospho-AKT and phospho-ERK signaling in response to SDF-1a in S338X CXCR4 mutated cells. Both AKT and ERK are major survival factors for malignant B-cell lymphomas.
From a translational view point, these finding of CXCR4 mutations are important since inhibitors for CXCR4 signaling are either approved by the FDA (plerixafor) or currently in clinical trials. Despite the more aggressive presentation associated with CXCR4 mutations, the presence of CXCR4 mutations did not impact survival, whereas having wild-type (no L265P) MYD88 mutation was associated with decreased survival. The reported findings from these studies have important implications for the individualized care of patients with WM based on their MYD88 L265P and CXCR4 mutational status, and provide a paradigm of how sequencing MYD88 and CXCR4 can provide clinically meaningful information for directing WM care. These studies also highlight the need to better understand and improve treatment for patients without the MYD88 L265P mutation (wild-type). The studies were funded by Dr. Peter Bing, the International Waldenström’s Macroglobulinemia Foundation, the Coyote Fund for WM, the D’Amato Family Fund for Genomic Discovery, and the Edward and Linda Nelson Fund for WM Research.