Details

Autor(en) / Beteiligte

• McDermott, David H.
• Gao, Ji-Liang
• Liu, Qian
• Siwicki, Marie
• Martens, Craig
• Jacobs, Paejonette
• Velez, Daniel
• Yim, Erin
• Bryke, Christine R.
• Hsu, Nancy
• Dai, Zunyan
• Marquesen, Martha M.
• Stregevsky, Elina
• Kwatemaa, Nana
• Theobald, Narda
• Long Priel, Debra A.
• Pittaluga, Stefania
• Raffeld, Mark A.
• Calvo, Katherine R.
• Maric, Irina
• Desmond, Ronan
• Holmes, Kevin L.
• Kuhns, Douglas B.
• Balabanian, Karl
• Bachelerie, Françoise
• Porcella, Stephen F.
• Malech, Harry L.
• Murphy, Philip M.

Titel

Chromothriptic Cure of WHIM Syndrome

Ist Teil von

• Cell, 2015-02, Vol.160 (4), p.686-699

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2015

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• Chromothripsis is a catastrophic cellular event recently described in cancer in which chromosomes undergo massive deletion and rearrangement. Here, we report a case in which chromothripsis spontaneously cured a patient with WHIM syndrome, an autosomal dominant combined immunodeficiency disease caused by gain-of-function mutation of the chemokine receptor CXCR4. In this patient, deletion of the disease allele, CXCR4R334X, as well as 163 other genes from one copy of chromosome 2 occurred in a hematopoietic stem cell (HSC) that repopulated the myeloid but not the lymphoid lineage. In competitive mouse bone marrow (BM) transplantation experiments, Cxcr4 haploinsufficiency was sufficient to confer a strong long-term engraftment advantage of donor BM over BM from either wild-type or WHIM syndrome model mice, suggesting a potential mechanism for the patient’s cure. Our findings suggest that partial inactivation of CXCR4 may have general utility as a strategy to promote HSC engraftment in transplantation. [Display omitted] [Display omitted] •CXCR4 haploinsufficiency may promote HSC engraftment•Chromothriptic deletions result in functional cure of WHIM syndrome•Clinical symptoms in WHIM syndrome are dependent on myeloid deficits•Myeloid-derived cells are critical for control of HPV infection WHIM syndrome is an inherited immunodeficiency caused by overactivity of CXCR4, a receptor controlling production and distribution of leukocytes in bone marrow and blood. We identified a WHIM patient cured by chromothripsis (chromosome shattering) that fortuitously deleted the abnormal copy of the CXCR4 gene in a single hematopoietic stem cell, which then took over the bone marrow and restored normal immune function. This experiment of nature suggests that partial CXCR4 inactivation might enhance engraftment of bone marrow in patients requiring transplantation.