The DOI matches its Crossref record; 106 of the 107 references it cites were found in a registry or an index, and 1 are not checked yet; none of the 112 sources its claims cite is checked for support yet.
Finding the needle in the hay stack: Hematopoietic stem cells in Fanconi anemia
Open accessAbstract
Fanconi anemia is a rare bone marrow failure and cancer predisposition syndrome. Childhood onset of aplastic anemia is one of the hallmarks of this condition. Supportive therapy in the form of blood products, androgens, and hematopoietic growth factors may boost blood counts temporarily. However, allogeneic hematopoietic stem cell transplantation (HSCT) currently remains the only curative treatment option for the hematologic manifestations of Fanconi anemia (FA). Here we review current clinical and pre-clinical strategies for treating hematopoietic stem cell (HSC) failure, including the experience with mobilizing and collecting CD34+ hematopoietic stem and progenitor cells as target cells for somatic gene therapy, the current state of FA gene therapy trials, and future prospects for cell and gene therapy.
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TL;DR
Fanconi anemia (FA) is a rare inherited bone marrow failure and cancer predisposition syndrome in which hematopoietic stem cells are progressively lost, and allogeneic HSCT remains the only curative treatment for hematologic manifestations. This review summarizes clinical and preclinical strategies for FA HSC failure, including CD34+ mobilization, gene therapy trials, and emerging cell/gene therapy approaches.
Key findings
- FA affects about 1 in 100,000 births; bone marrow failure has a median onset of eight years, 90% of patients develop it by age 40, and AML incidence is 33% by age 40.
- Allogeneic HSCT remains the only curative option for hematologic FA; matched sibling transplant 5-year survival is approximately 85%, but <30% of patients have an HLA-identical sibling donor, while fludarabine-containing unrelated donor regimens achieved 52% overall survival at 3 years in a retrospective review of 98 patients.
- FA patients have a paucity of CD34+ HSC/P: compared with normal controls, FA patients had a 2-fold reduction in marrow cellularity and a 6-fold reduction in CD34+ cells; in one collection study, the target of 2×10^6 CD34+ cells/kg future weight was not obtained in any patient, though all four attained that dose based on entry weight.
- Two clinical FA gene therapy trials in 7 patients with FANCA/FANCC mutations established feasibility of gammaretroviral gene transfer, with in vitro transduction rates of 10–20% and 42–62%, but neither achieved prolonged engraftment of gene-modified HSC; infused cell doses were up to 50-fold less than in clinically efficacious immunodeficiency gene therapy trials.
Methods
- Narrative review of current clinical and preclinical strategies for treating hematopoietic stem cell failure in FA, including mobilization and collection of CD34+ cells, FA gene therapy trials, and future cell and gene therapy prospects.
- Evidence synthesized from published clinical studies, two FA gene therapy trials totaling 7 patients, mobilization/collection studies in FA patients, murine FA models (Fanca−/− and Fancc−/−), and cited basic and translational literature.
- No systematic review methodology, search strategy, or meta-analysis is described.
Limitations
- The paper states that murine FA models fail to faithfully recapitulate all aspects of human disease and do not develop a bone marrow failure phenotype under steady-state conditions; the relevance of TNF-α-induced leukemic clonal evolution to the human system is unknown; no data on iPS technology applicability to FA have been published; and efficacy/safety of safety-modified vectors has yet to be established in clinical trials.
- Evident from the text: this is a narrative review without systematic search or formal quality assessment, relying on heterogeneous preclinical studies and small clinical series, and it reports no new primary data.
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40 Check pending · 21 No full text of the sources · 10 Own interpretation · 1 Not checked yet · 1 No basis given
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In the paper
“taken together, these data suggest that pro-apoptotic cytokines are potential contributing factors to HSC failure and leukemogenesis in FA.”
§ Finding the needle in the hay stack: Hematopoietic stem cells in Fanconi anemia > 2. The effect of pro-apoptotic cytokines on Fanconi anemia HSC
hedgedstates a possible causen = 12- Asserted: passes — The authors put it forward as true.
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In the paper
“Avoidance of blood transfusions is critical whenever possible, since even relatively modest blood component exposure has been shown to have a negative impact on the outcomes of allogeneic bone marrow transplantation[22].”
§ Finding the needle in the hay stack: Hematopoietic stem cells in Fanconi anemia > 3. Clinical challenges of hematopoietic stem cell failure in Fanconi anemia
What the sources say
- Check pendingcites [22] Wagner, 2007, Unrelated donor bone marrow transplantation for the treatment of Fanconi anemia, Blood source
boostedstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“In Fancc−/− mice, TNF-α and INF-γ induce apoptosis in hematopoietic progenitor cells, even at low cytokine levels[16–18].”
§ Finding the needle in the hay stack: Hematopoietic stem cells in Fanconi anemia > 2. The effect of pro-apoptotic cytokines on Fanconi anemia HSC
What the sources say
- Not checked — no full text of the sourcecites [16] Rathbun, 1997, Inactivation of the Fanconi anemia group C gene augments interferon-gamma-induced apoptotic responses in hematopoietic cells, Blood source
- Check pendingcites [17] Whitney, 1996, Germ cell defects and hematopoietic hypersensitivity to gamma-interferon in mice with a targeted disruption of the Fanconi anemia C gene, Blood source
- Not checked — no full text of the sourcecites [18] Haneline, 1998, Multiple inhibitory cytokines induce deregulated progenitor growth and apoptosis in hematopoietic cells from Fac-/- mice, Blood source
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Currently, the 5-year survival rate after matched sibling transplant is approximately 85%[29,30].”
§ Finding the needle in the hay stack: Hematopoietic stem cells in Fanconi anemia > 3. Clinical challenges of hematopoietic stem cell failure in Fanconi anemia
What the sources say
- Not checked — no full text of the sourcecites [29] Gluckman, 1995, Bone marrow transplantation for Fanconi anemia, Blood source
- Not checked — no full text of the sourcecites [30] Farzin, 2007, Matched sibling donor haematopoietic stem cell transplantation in Fanconi anaemia: an update of the Cincinnati Children's experience, Br. J. Haematol. source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“These severe adverse events are now understood to result from “side effects” of viral integration into the genome.”
§ Finding the needle in the hay stack: Hematopoietic stem cells in Fanconi anemia > 4. The coming of age of gene therapy: From the bench to the bed-side and back
What the sources say
- Not checked — no full text of the sourcecites [44] Li, 2002, Murine leukemia induced by retroviral gene marking, Science source
- Check pendingcites [45] Modlich, 2006, Cell culture assays reveal the importance of retroviral vector design for insertional genotoxicity, Blood source
- Not checked — no full text of the sourcecites [46] Kustikova, 2005, Clonal dominance of hematopoietic stem cells triggered by retroviral gene marking, Science source
plainstates a causen = 5- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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- Probably not a substantial claim. 12
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Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Finding the needle in the hay stack: Hematopoietic stem cells in Fanconi anemia > 1. Introduction
“Other organ systems involved include the cardiac, renal, and auditory systems[1] (in press, Mutation Research, 2009).”
§ Finding the needle in the hay stack: Hematopoietic stem cells in Fanconi anemia > References
“1. Alter BP Rosenberg PS Granulocyte colony-stimulating factor and severe aplastic anemia Blood 109 2007 4589 author reply 4589–4590 17483301”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Finding the needle in the hay stack: Hematopoietic stem cells in Fanconi anemia > 5. Rational for Fanconi anemia gene therapy
“Ex vivo gene transfer into HSC of gene targeted FA mice has been shown to correct the cellular FA phenotype at the level of long term repopulating stem cells [33,60–62].”
§ Finding the needle in the hay stack: Hematopoietic stem cells in Fanconi anemia > References
“60. Liu G Excoffon KJ Benoit P Ginzinger DG Miao L Ehrenborg E Duverger N Denefle PP Hayden MR Lewis ME Efficient adenovirus-mediated ectopic gene expression of human lipoprotein lipase in human hepatic (HepG2) cells Hum Gene Ther 8 1997 205 214 9017424”
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Metadata
- Authors
- Müller, L. U. W., & Williams, D. A.
- Affiliations
- Boston Children's Hospital (US)
- Corresponding author
- Williams, David A.
- ORCID
- Williams, David A.
- Venue
- Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
- Publisher
- Elsevier BV
- Published
- 2009-07
- Volume
- 668
- Issue
- 1-2
- Pages
- 141-149
- ISSN
- 0027-5107 (ISSN-L)
- 1386-1964
- PMC
- PMC2815349
- OpenAlex
- W2066658273
- Cited by
- 31
- References
- 107
- Citations by year
- 2024: 2 · 2021: 3 · 2020: 1 · 2018: 4 · 2017: 2 · 2016: 1 · 2015: 3 · 2013: 2 · 2012: 2
- FWCI
- 0.65
- Type
- journal article
- Language
- en
- Open access
- green
- pmc.ncbi.nlm.nih.gov
- Licence
- Locations
- Mutation research. Fundamental and molecular mechanisms of mutagenesis (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (DK074310, R01 HL081499)
- St. Baldrick's Foundation
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Health Sciences › Medicine › Hematology › Blood disorders and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Keywords
- Fanconi anemia, hematopoietic stem cells, aplastic anemia, bone marrow failure, allogeneic hematopoietic stem cell transplantation, CD34+ hematopoietic stem and progenitor cells, somatic gene therapy, gene therapy clinical trials, cell and gene therapy, cancer predisposition syndromes
- MeSH terms
- Animals, Bone Marrow Diseases, Fanconi Anemia, Forecasting, Genetic Therapy, Cytokines, Hematopoietic Stem Cell Transplantation, Hematopoietic Stem Cell Mobilization, Cell- and Tissue-Based Therapy
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