February 23, 2015

Rare Immune Disease Cured by Random Genetic Event

At a Glance

  • The first person to be documented with WHIM syndrome was spontaneously cured by a cellular event normally considered catastrophic.
  • In addition to giving insight into WHIM syndrome, the mechanism of the cure may lead to improved bone marrow transplantation.
Chromosomes. An image of all 46 chromosomes of the cured WHIM syndrome patient shows that one copy of chromosome 2 (red box) is significantly shorter than the other, a loss of genetic material caused by chromothripsis. This random event fortuitously deleted a mutant copy of the gene responsible for WHIM syndrome in the immune cells most affected by the mutation.NIAID

WHIM syndrome is a rare genetic disease of the immune system. WHIM is named for its main manifestations: Warts, Hypogammaglobulinemia (an antibody deficiency), Infections, and Myelokathexis (failure of immune cells called neutrophils to move from bone marrow to the bloodstream). Patients are especially prone to human papillomavirus (HPV) infections, which cause skin and genital warts and can lead to cancer. WHIM syndrome has no approved treatments, but a promising drug is now being evaluated.

WHIM syndrome was first described in 1964. Its underlying genetic mutations were identified in 2003. These occur in the CXC chemokine receptor 4 (CXCR4) gene. One function of CXCR4 is to tether immune cells to the bone marrow. WHIM mutations result in excessive CXCR4 activity, which can trap the immune cells and keep them from moving to the bloodstream. The mutations behind WHIM are dominant, meaning they cause disease even if another fully functional copy of the gene is present.

The first patient diagnosed with WHIM  syndrome in the 1964 paper, now 60 years old, recently contacted NIH’s National Institute of Allergy and Infectious Diseases (NIAID) about herself and 2 of her children, who were also diagnosed with WHIM syndrome. The patient reported that her symptoms had resolved when she was in her 30s. She’d remained disease free for nearly 20 years. An NIAID research team led by Dr. Philip Murphy evaluated the patient for clues to this spontaneous cure. The report appeared in Cell on February 12, 2015.

The researchers identified chromothripsis—the abrupt fragmentation of a chromosome, with subsequent deletions and rearrangements—as the likely reason for the cure. Chromothripsis was first reported in 2011 in association with cancer. In this case, a random, fortuitous event deleted a part of the chromosome with the mutant CXCR4 gene and 163 other known genes. A functional copy of these genes remained on the other chromosome. While neutrophils and related cells from the patient had the chromothriptic chromosome, lymphocytes (another type of immune cell) didn’t. This suggests that the rare event occurred in a stem cell that selectively repopulated the patient with neutrophils lacking mutant CXCR4.

In a mouse model of WHIM, the researchers found that stem cells with only one functional copy of Cxcr4 had an engraftment advantage during bone marrow transplantation. The cells grew and established new blood cells more effectively than cells with 2 functional copies of Cxcr4 or cells with both a normal and a hyperactive copy. This finding suggests a way to improve bone marrow transplantation, which relies on the ability of donor stem cells to engraft. The team is now further exploring this strategy.

These results don’t rule out the possibility that some of the other 163 deleted genes contributed to the patient’s cure. Regardless of what combination of genes proves to be responsible, the study is the first to link chromothripsis to a positive outcome.

“There are cases that are sometimes referred to as ‘miracle cases’ or patients who ‘outgrew’ their disease,” Murphy says. “One of the points of our study is that anybody who has such a patient should now consider chromothripsis as a potential natural explanation for recovery.”

—by Harrison Wein, Ph.D.

Related Links

Reference: Chromothriptic cure of WHIM syndrome. McDermott DH, Gao JL, Liu Q, Siwicki M, Martens C, Jacobs P, Velez D, Yim E, Bryke CR, Hsu N, Dai Z, Marquesen MM, Stregevsky E, Kwatemaa N, Theobald N, Long Priel DA, Pittaluga S, Raffeld MA, Calvo KR, Maric I, Desmond R, Holmes KL, Kuhns DB, Balabanian K, Bachelerie F, Porcella SF, Malech HL, Murphy PM. Cell. 2015 Feb 12;160(4):686-99. doi: 10.1016/j.cell.2015.01.014. Epub 2015 Feb 5. PMID: 25662009.

Funding: NIH’s National Institute of Allergy and Infectious Diseases (NIAID) and National Cancer Institute (NCI).