Affinage

CCDC28A

Coiled-coil domain-containing protein 28A · UniProt Q8IWP9

Length
274 aa
Mass
30.4 kDa
Annotated
2026-06-09
16 papers in source corpus 6 papers cited in narrative 6 extracted findings
Cross-family judge faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CCDC28A is a coiled-coil domain protein with two distinct biological identities: a germ-cell-specific role in sperm morphogenesis and a recurrent role as an oncogenic fusion partner in myeloid leukemia. In the testis, CCDC28A is expressed specifically in male germ cells, and its loss in knockout mice produces male infertility characterized by bent sperm heads, acrosomal defects, reduced motility, and disruption of the head-tail coupling apparatus at the capitulum-basal plate junction, while the axoneme, outer dense fibers, and fibrous sheath remain intact (PMID:38597936, PMID:39500989). Consistent with a structural/scaffolding role in sperm head-tail integrity and acrosome formation, CCDC28A physically interacts with SPACA1 and GSK3A (PMID:38597936). Independently, CCDC28A is recurrently fused to NUP98 and to NPM1 in acute myeloid leukemia (PMID:16028218, PMID:34343258). The NUP98-CCDC28A fusion is a bona fide oncogene that, upon expression in murine bone marrow, induces a transplantable myeloid neoplasm and selectively expands granulocyte/macrophage progenitors independently of Hoxa-Meis1 deregulation (PMID:22058212). The NPM1-CCDC28A fusion contributes a nuclear export signal that drives cytoplasmic mislocalization of NPM1 (NPM1c+), immortalizes bone marrow cells, and induces AML in vivo; mechanistically it binds HOX cluster chromatin and aberrantly upregulates HOX genes in an XPO1-dependent manner, conferring sensitivity to the XPO1 inhibitor selinexor and to menin inhibition (PMID:34343258, PMID:39443736). The molecular biochemistry of the native CCDC28A protein beyond these interactions and fusion contexts has not been characterized in the available corpus.

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2005 Medium

    Established CCDC28A as a recurrent partner in chromosomal translocation, linking the previously uncharacterized gene to leukemia for the first time.

    Evidence FISH and RT-PCR identifying the NUP98-CCDC28A fusion transcript in a t(6;11) acute megakaryoblastic leukemia case

    PMID:16028218

    Open questions at the time
    • Single case report; did not test whether the fusion is functionally transforming
    • No information on normal CCDC28A function
  2. 2011 High

    Demonstrated that the NUP98-CCDC28A fusion is causally oncogenic, transforming myeloid progenitors and distinguishing it mechanistically from Hox-deregulating NUP98 fusions.

    Evidence Retroviral transduction of murine bone marrow followed by transplantation, with flow cytometry of progenitor populations

    PMID:22058212

    Open questions at the time
    • The molecular target of the fusion was not identified
    • Mechanism of progenitor self-renewal not resolved
  3. 2021 Medium

    Identified a second oncogenic fusion, NPM1-CCDC28A, and showed CCDC28A supplies a nuclear export signal driving cytoplasmic NPM1 accumulation, the hallmark of NPM1-mutant AML biology.

    Evidence Immunohistochemistry for cytoplasmic NPM1, RNA-seq, and functional NES assays in AML samples

    PMID:34343258

    Open questions at the time
    • Did not establish downstream transcriptional consequences
    • In vivo transforming capacity not yet tested at this stage
  4. 2024 High

    Defined the downstream mechanism of NPM1-CCDC28A: XPO1-dependent HOX cluster chromatin binding and HOX upregulation drive leukemogenesis, revealing actionable drug dependencies.

    Evidence Subcellular localization, bone marrow immortalization, mouse AML transplantation, chromatin binding assay, and selinexor/menin inhibitor sensitivity

    PMID:39443736

    Open questions at the time
    • Direct DNA-binding versus recruitment of the fusion to HOX chromatin not fully dissected
    • Contribution of the CCDC28A coiled-coil moiety to chromatin targeting not isolated
  5. 2024 High

    Established the physiological function of native CCDC28A as a germ-cell factor required for sperm head-tail coupling apparatus integrity and acrosome formation, with defined physical partners.

    Evidence Knockout mouse with sperm morphology, IVF assays, TEM ultrastructure, and co-IP identifying SPACA1 and GSK3A interactions; two concurrent independent studies

    PMID:38597936 PMID:39500989

    Open questions at the time
    • Molecular activity of CCDC28A (structural scaffold vs. regulator) not defined
    • Functional consequence of the GSK3A interaction not established
    • Subcellular localization within germ cells not precisely mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the normal scaffolding/germ-cell function of CCDC28A relates to its capacity to act as a transforming fusion partner — and what the protein's intrinsic biochemical activity is — remains unknown.
  • No structural model of CCDC28A
  • No defined molecular activity for the native protein
  • Relationship between germ-cell and leukemic functions uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Pathway
R-HSA-1643685 Disease 4 R-HSA-1474165 Reproduction 2
Partners
GSK3ANPM1NUP98SPACA1XPO1

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 CCDC28A (C6orf80) was identified as a fusion partner of NUP98 in a novel t(6;11)(q24.1;p15.5) translocation in a patient with acute megakaryoblastic leukemia; RT-PCR confirmed expression of the NUP98-C6orf80 (NUP98-CCDC28A) fusion transcript. Molecular cytogenetics (FISH), reverse-transcription PCR Genes, chromosomes & cancer Medium 16028218
2011 The NUP98-CCDC28A fusion protein was shown to function as an oncogene: retroviral transduction into primary murine bone marrow cells followed by transplantation induced a fully penetrant, transplantable myeloproliferative neoplasm-like myeloid leukemia, and caused selective expansion of granulocyte/macrophage progenitors, demonstrating that NUP98-CCDC28A promotes proliferative capacity and self-renewal potential of myeloid progenitors. Notably, this transformation was not associated with deregulation of the Hoxa-Meis1 pathway, distinguishing it mechanistically from other NUP98 fusions. Retroviral transduction of murine bone marrow cells, mouse transplantation assay, flow cytometry of bone marrow progenitors Haematologica High 22058212
2021 The NPM1-CCDC28A fusion protein was identified in AML samples and shown to harbor an efficient nuclear export signal (NES), either newly created or already present in the fusion partner, ensuring cytoplasmic accumulation of the NPM1 fusion protein (NPM1c+), as detected by immunohistochemistry and functional studies. Immunohistochemistry for cytoplasmic NPM1, RNA sequencing, functional studies of NES activity Blood Medium 34343258
2024 NPM1::CCDC28A fusion protein is more localized to the cytoplasm than NPM1::MLF1, immortalizes mouse bone marrow cells in vitro, and efficiently induces AML in vivo in a mouse transplantation assay. Mechanistically, NPM1::CCDC28A binds to HOX gene cluster chromatin and causes aberrant upregulation of HOX genes in cooperation with XPO1 (similar to NPM1c). The XPO1 inhibitor selinexor suppressed HOX activation and colony formation. NPM1::CCDC28A cells were also sensitive to menin inhibition. Subcellular localization assays, mouse bone marrow immortalization assay, mouse transplantation assay, ChIP or chromatin binding assay, pharmacological inhibition (selinexor, menin inhibitor), gene expression analysis Leukemia High 39443736
2024 CCDC28A is highly expressed in testes; its deletion in mice causes male infertility with bent sperm heads, acrosomal defects, reduced sperm motility, and decreased in vitro fertilization competence, while axoneme, outer dense fibers, and fibrous sheath remain normal. CCDC28A was shown to physically interact with sperm acrosome membrane-associated protein 1 (SPACA1) and glycogen synthase kinase 3a (GSK3A). Knockout mouse model, sperm morphology analysis, in vitro fertilization assay, co-immunoprecipitation/interaction assay for SPACA1 and GSK3A Cellular and molecular life sciences : CMLS High 38597936
2024 CCDC28A is expressed specifically in male germ cells (not in supporting somatic cells), and its deficiency in knockout mice causes diminished sperm motility and structural disruption of the head-tail coupling apparatus (HTCA), specifically at the capitulum-basal plate junction, leading to head bending within the neck region and thickening of the tail midpiece, and male infertility. Knockout mouse model, histological analyses, transmission electron microscopy, expression pattern analysis Scientific reports High 39500989

Source papers

Stage 0 corpus · 16 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 NUP98 rearrangements in hematopoietic malignancies: a study of the Groupe Francophone de Cytogénétique Hématologique. Leukemia 108 16467868
2019 Transcriptome analysis offers a comprehensive illustration of the genetic background of pediatric acute myeloid leukemia. Blood advances 75 31648321
2018 The genetics and clinical characteristics of children morphologically diagnosed as acute promyelocytic leukemia. Leukemia 58 30575821
2021 Novel NPM1 exon 5 mutations and gene fusions leading to aberrant cytoplasmic nucleophosmin in AML. Blood 47 34343258
2007 Fusion of NUP98 and the SET binding protein 1 (SETBP1) gene in a paediatric acute T cell lymphoblastic leukaemia with t(11;18)(p15;q12). British journal of haematology 43 17233820
2005 Characterization of 6q abnormalities in childhood acute myeloid leukemia and identification of a novel t(6;11)(q24.1;p15.5) resulting in a NUP98-C6orf80 fusion in a case of acute megakaryoblastic leukemia. Genes, chromosomes & cancer 17 16028218
2011 Functional analysis of the NUP98-CCDC28A fusion protein. Haematologica 15 22058212
2024 NPM1-fusion proteins promote myeloid leukemogenesis through XPO1-dependent HOX activation. Leukemia 12 39443736
2020 A Protein Microarray-Based Investigation of Cerebrospinal Fluid Reveals Distinct Autoantibody Signature in Low and High-Grade Gliomas. Frontiers in oncology 10 33415070
2013 Identification of multiple complex rearrangements associated with deletions in the 6q23-27 region in Sézary syndrome. The Journal of investigative dermatology 10 23698072
2024 CCDC28A deficiency causes sperm head defects, reduced sperm motility and male infertility in mice. Cellular and molecular life sciences : CMLS 8 38597936
2023 Immune Cell Infiltration Analysis Based on Bioinformatics Reveals Novel Biomarkers of Coronary Artery Disease. Journal of inflammation research 5 37525634
2024 CCDC28A deficiency causes head-tail coupling defects and immotility in murine spermatozoa. Scientific reports 3 39500989
2025 A new perspective on endometriosis: Integrating eQTL mendelian randomization with transcriptomics and single-cell data analyses. Functional & integrative genomics 1 40140093
2026 NPM1-rearranged AML: clinical features, molecular pathogenesis, and therapeutic perspectives. International journal of hematology 0 42247117
2025 Concurrent NPM1::CCDC28A and BCR::ABL1 fusions in extramedullary blast crisis of chronic myeloid leukemia: A case report and literature review. Annals of hematology 0 41120674

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