NIH: The world of biomedical research is filled with surprises. Here’s a remarkable one published recently in the journal Cell
[1]. A child born in the 1950s with a rare genetic immunodeficiency
syndrome amazingly cured herself years later when part of one of her
chromosomes spontaneously shattered into 18 pieces during replication of
a blood stem cell. The damaged chromosome randomly reassembled, sort of
like piecing together a broken vase, but it was still missing a shard
of 164 genes—including the very gene that caused her condition.
Researchers say the chromosomal shattering probably took place in a
cell in the bone marrow. The stem cell, now without the disease-causing
gene, repopulated her immune system with healthy bone marrow-derived
immune cells, resulting in cure of the syndrome.
How is this possible? The research story
begins a couple of years ago when the woman, now 59, contacted
researchers at NIH’s National Institute of Allergy and Infectious
Diseases (NIAID), who study a rare immunodeficiency known as WHIM
syndrome. The woman reported that she and two of her daughters had the
autosomal dominant disorder.
It isn’t every day that researchers get a call out of the blue from
someone with WHIM syndrome: fewer than 60 cases have been diagnosed
worldwide over the past 50 years. The interaction took an even more
interesting turn when the researchers learned that the mother was the
first person ever diagnosed with the condition as a child in 1964 [2,
3]. She’d been through the wringer with the syndrome, battling its
puzzling manifestations of serious recurrent infections and skin warts
caused by an unexplained susceptibility to the human papillomavirus.
When asked how she was doing now, the mother responded that the
syndrome had vanished during her 30s. Philip Murphy, a NIAID
immunologist, said he was floored by her comment—it just didn’t seem
medically possible.
Everyone is born with two copies of a gene called CXCR4.
The gene encodes a cell-surface receptor that mediates immune
signaling. But people born with WHIM syndrome inherit one normal and one
mutant copy of the gene [4]. The garbled gene yields an abnormal
receptor that signals excessively on the surface of white blood cells.
It’s like a car with the accelerator stuck. The excess signaling blocks
the ability of the young white blood cells in the bone marrow
(monocytes and neutrophils) to mature, preventing an adequate supply
from entering the blood stream to help fight off infections.
After some initial tests on the family, Murphy and his colleagues
noted that the mother’s white cells were no longer deficient in numbers –
which is not expected in WHIM syndrome. They reasoned that the only
way the mother could have been cured was if the mutant copy of her CXCR4
gene was lost somehow. So David McDermott and Joy Liu from Murphy’s lab
examined the woman’s white blood cells, and sure enough, the abnormal
copy was gone. But when they examined cells from other tissues of her
body, the mutant gene was still present. That’s how two of her three
daughters inherited the condition.
With further DNA testing, the NIAID team noticed a truncated and
massively rearranged chromosome 2 (shown in the image above) in the
mother’s white cells (but not in cells from her skin). They developed a
solid but rather astonishing explanation. Years ago, they deduced that
in a single blood-forming stem cell in the woman’s marrow, part of
chromosome 2 must have undergone a major breakage and reassembly. The
name of this phenomenon is chromothripsis, which in Greek means “a
chromosome shattering into pieces.”
Chromothripsis was originally identified in cancer cells, and is now
known to occur in about 2 percent of cancers. Since then, it’s also been
identified in a patient with severe congenital cognitive syndrome. What
scientists had not imagined is that such a cataclysmic event could
actually cure a disease. Murphy hypothesized that the loss of the mutant
CXCR4 gene gave a stem cell an advantage to grow, divide, and
eventually replace all of the woman’s stem cells carrying the WHIM
harmful mutation.
There currently are no approved treatments for WHIM syndrome. But
knowing about this unique case suggests that manipulation of bone marrow
stem cells to inactivate the mutant gene, perhaps using the CRISPR-Cas
system (See “Copy-Editing the Genome“),
might provide a new strategy in the future. Researchers also suggest
that the findings might also help improve bone marrow transplantation,
which relies on the ability of donor stem cells to repopulate in a
transplant recipient.
References:
[1] 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.
[2] “Myelokathexis’’– A New Form of Chronic Granulocytopenia. Report of a Case. Zuelzer WW. N Engl J Med. 1964 Apr 2;270:699-704.
[3] Chronic Idiopathic Granulocytopenia. Krill CE Jr, Smith HD, Mauer AM. N Engl J Med. 1964 May 7;270:973-9.
[4] Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease. Hernandez PA, Gorlin RJ, Lukens JN, Taniuchi S, Bohinjec J, Francois F, Klotman ME, Diaz GA. Nat Genet. 2003 May;34(1):70-4.
Links:
Primary Immunodeficiency (Eunice Kennedy Shriver National Institute of Child Health and Development/NIH)
Office of Rare Diseases (National Center for Advancing Translational Sciences/NIH)
Philip M. Murphy, National Institute of Allergy and Infectious Diseases, Bethesda
NIH Support: National Institute of Allergy and Infectious
Diseases; National Cancer Institute; National Heart, Lung, and Blood
Institute