Low-level Cxcr4-haploinsufficient HSC engraftment is sufficient to correct leukopenia in WHIM syndrome mice

Gao, Ji-Liang; Owusu-Ansah, Albert; Paun, Andrea; Beacht, Kimberly; Yim, Erin; Siwicki, Marie; Yang, Alexander; Liu, Qian; McDermott, David H.; Murphy, Philip M.

doi:10.1172/jci.insight.132140

Cited by 5 publications

(4 citation statements)

References 29 publications

(50 reference statements)

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“…This observation may suggest that a fine-tune regulation of the levels of CXCR4 surface expression is key for the maintenance of a physiological HSPC homeostasis, as its dramatic and sustained overexpression could be detrimental to this process. Notably, reduction of CXCR4 expression 30 , 31 has been associated to enhanced BM engraftment of human HSCs. 30 , 31 …”

Section: Discussionmentioning

confidence: 99%

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Prostaglandin E2 as transduction enhancer affects competitive engraftment of human hematopoietic stem and progenitor cells

Poletti,

Montepeloso,

Pellin

et al. 2023

Molecular Therapy - Methods & Clinical Development

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Section: Discussionmentioning

confidence: 99%

“…Notably, reduction of CXCR4 expression 30 , 31 has been associated to enhanced BM engraftment of human HSCs. 30 , 31 …”

Section: Discussionmentioning

confidence: 99%

Prostaglandin E2 as transduction enhancer affects competitive engraftment of human hematopoietic stem and progenitor cells

Poletti,

Montepeloso,

Pellin

et al. 2023

Molecular Therapy - Methods & Clinical Development

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“…Regular plerixafor therapy does not seem to completely resolve all disease complications [ 19 ], while our transplantation experience demonstrates complete resolution of the majority of disease symptoms. Although there is evidence of possible gene therapy efficacy in WHIM syndrome mouse models [ 29 ], so far, allogeneic HSCT remains the only curative option for WHIM syndrome patients. Therefore, based on our experience of HSCT and subsequent short-term follow-up, we believe that HSCT can be considered as a treatment option for WHIM syndrome, including pre-emptive indications in younger patients, before they develop autoimmunity and malignancies at an older age.…”

Section: Discussionmentioning

confidence: 99%

Multicenter Experience of Hematopoietic Stem Cell Transplantation in WHIM Syndrome

Laberko

Deordieva

Kriván³

et al. 2021

J Clin Immunol

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Purpose WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome is a rare disease, caused by CXCR4 gene mutations, which incorporates features of combined immunodeficiency, congenital neutropenia, and a predisposition to human papillomavirus infection. Established conventional treatment for WHIM syndrome does not fully prevent infectious complications in these patients. Only single case reports of hematopoietic stem cell transplantation (HSCT) efficacy in WHIM have been published. Methods To summarize current information on HSCT efficacy in disease treatment, seven pediatric patients with WHIM syndrome who underwent allogeneic HSCT were identified in five centers worldwide. Results All patients presented early after birth with neutropenia. Two of seven patients exhibited severe disease complications: poorly controlled autoimmunity (arthritis and anemia) in one and progressive myelofibrosis with recurrent infections in the other. The remaining patients received HSCT to correct milder disease symptoms (recurrent respiratory infections, progressing thrombocytopenia) and/or to preclude severe disease course in older age. All seven patients engrafted but one developed graft rejection and died of infectious complications after third HSCT. Three other patients experienced severe viral infections after HSCT (including post-transplant lymphoproliferative disease in one) which completely resolved with therapy. At last follow-up (median 6.7 years), all six surviving patients were alive with full donor chimerism. One patient 1.4 years after HSCT had moderate thrombocytopenia and delayed immune recovery; the others had adequate immune recovery and were free of prior disease symptoms. Conclusion HSCT in WHIM syndrome corrects neutropenia and immunodeficiency, and leads to resolution of autoimmunity and recurrent infections, including warts.

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“…In AD SCN, recent evidence suggests deletion of the disease allele may be a simple and effective technique without need to specifically correct the gene defect. In the case of WHIM syndrome, evidence suggests that removal of one copy of CXCR4 enhances haematopoietic stem cell engraftment and survival without the need for conditioning 14 . Similarly, editing and removal of ELANE may be curative in the future 15 …”

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confidence: 99%

JAGN1 mutations in severe congenital neutropenia

McDermott

Malech

2020

Br J Haematol

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Low-level Cxcr4-haploinsufficient HSC engraftment is sufficient to correct leukopenia in WHIM syndrome mice

Cited by 5 publications

References 29 publications

Prostaglandin E2 as transduction enhancer affects competitive engraftment of human hematopoietic stem and progenitor cells

Prostaglandin E2 as transduction enhancer affects competitive engraftment of human hematopoietic stem and progenitor cells

Multicenter Experience of Hematopoietic Stem Cell Transplantation in WHIM Syndrome

JAGN1 mutations in severe congenital neutropenia

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