Affinage

CCDC28A

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

Length
274 aa
Mass
30.4 kDa
Annotated
2026-04-28
15 papers in source corpus 6 papers cited in narrative 6 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CCDC28A is a coiled-coil domain-containing protein with dual roles: in male germ cells it is essential for sperm head-tail coupling apparatus (HTCA) integrity, acrosome formation, and motility, while in somatic cells it participates in oncogenic fusions driving myeloid leukemia. In the testis, CCDC28A physically interacts with SPACA1 and GSK3A, and its loss in knockout mice causes structural disruption of the capitulum–basal plate junction, bent sperm heads, thickened midpieces, and male infertility (PMID:38597936, PMID:39500989). CCDC28A is recurrently rearranged as a fusion partner of NUP98 and NPM1 in acute myeloid leukemia; the NPM1::CCDC28A fusion drives cytoplasmic mislocalization of NPM1 via a nuclear export signal, binds HOX gene clusters, and upregulates HOX genes in an XPO1-dependent manner that is sensitive to selinexor and menin inhibition (PMID:39443736, PMID:34343258). The NUP98-CCDC28A fusion independently transforms myeloid progenitors through a mechanism distinct from the canonical Hoxa-Meis1 pathway (PMID:22058212).

Mechanistic history

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

    Identification of CCDC28A as a novel NUP98 fusion partner in acute megakaryoblastic leukemia established its potential involvement in leukemogenesis, though no functional role was yet defined.

    Evidence FISH and RT-PCR on patient samples carrying t(6;11)(q24.1;p15.5)

    PMID:16028218

    Open questions at the time
    • No functional assay for the fusion protein
    • Mechanism of transformation unknown
    • Single patient case
  2. 2011 High

    Demonstrating that the NUP98-CCDC28A fusion is a bona fide oncogene that transforms myeloid progenitors in vivo resolved whether this translocation is a driver versus passenger event, and revealed it operates through a non-canonical mechanism independent of Hoxa-Meis1.

    Evidence Retroviral transduction of murine bone marrow followed by transplantation into irradiated recipients

    PMID:22058212

    Open questions at the time
    • Alternative leukemogenic pathway downstream of NUP98-CCDC28A not identified
    • Normal function of CCDC28A protein not addressed
  3. 2021 Medium

    Characterization of the NPM1::CCDC28A fusion in AML showed that CCDC28A contributes a functional nuclear export signal, establishing cytoplasmic NPM1 mislocalization as a shared leukemogenic mechanism across NPM1 fusions.

    Evidence RNA sequencing, immunohistochemistry for NPM1 localization, and NES functional analysis in AML patient samples

    PMID:34343258

    Open questions at the time
    • Whether the NES derives from a de novo junction sequence or from CCDC28A itself was not fully resolved
    • Downstream effectors of cytoplasmic NPM1::CCDC28A not characterized
  4. 2024 High

    Mechanistic dissection of NPM1::CCDC28A revealed it binds HOX gene clusters and drives their XPO1-dependent upregulation, connecting the cytoplasmic mislocalization phenotype to a specific transcriptional oncogenic program and identifying actionable therapeutic vulnerabilities (selinexor, menin inhibition).

    Evidence In vitro immortalization, in vivo transplantation AML model, chromatin binding assay, pharmacological inhibition with selinexor and menin inhibitor

    PMID:39443736

    Open questions at the time
    • Whether the NUP98-CCDC28A fusion shares the HOX-dependent mechanism is unknown
    • Structural basis of NPM1::CCDC28A–chromatin interaction not determined
  5. 2024 High

    Knockout mouse studies established the first physiological role for CCDC28A: it is essential for HTCA formation, acrosome biogenesis, and sperm motility, interacting with SPACA1 and GSK3A to maintain the capitulum–basal plate junction.

    Evidence Two independent Ccdc28a knockout mouse models with sperm morphology, TEM ultrastructure, in vitro fertilization, and co-immunoprecipitation

    PMID:38597936 PMID:39500989

    Open questions at the time
    • Biochemical function of CCDC28A (enzymatic vs. scaffolding) not defined
    • How CCDC28A coordinates SPACA1 and GSK3A activities at the HTCA is unknown
    • Human male infertility caused by CCDC28A mutations not yet reported

Open questions

Synthesis pass · forward-looking unresolved questions
  • The intrinsic molecular activity of CCDC28A protein — whether it acts as a structural scaffold, signaling adaptor, or has other biochemical function — remains undefined, and no structure or enzymatic activity has been reported.
  • No crystal/cryo-EM structure available
  • No enzymatic or catalytic activity tested
  • Somatic cell function of wild-type CCDC28A is entirely uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Localization
GO:0005829 cytosol 2
Pathway
R-HSA-1474165 Reproduction 2 R-HSA-1643685 Disease 2
Partners
GSK3ANPM1NUP98SPACA1XPO1

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 NUP98-CCDC28A fusion protein acts as an oncogene: retroviral transduction of NUP98-CCDC28A into primary murine bone marrow cells followed by transplantation produced a fully penetrant, transplantable myeloproliferative neoplasm-like myeloid leukemia with selective expansion of granulocyte/macrophage progenitors, demonstrating that the fusion promotes proliferative capacity and self-renewal of myeloid progenitors. Notably, transformation by NUP98-CCDC28A was not associated with deregulation of the Hoxa-Meis1 pathway, indicating an alternative leukemogenic mechanism distinct from many other NUP98 fusions. Retroviral transduction of primary murine bone marrow cells, in vivo transplantation into sub-lethally irradiated recipients, in silico expression analysis Haematologica High 22058212
2024 NPM1::CCDC28A fusion protein localizes predominantly to the cytoplasm (more so 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 the HOX gene cluster and causes aberrant upregulation of HOX genes in cooperation with XPO1 (nuclear export factor), similar to NPM1c. The XPO1 inhibitor selinexor suppressed HOX activation and colony formation, and NPM1::CCDC28A cells were also sensitive to menin inhibition. Subcellular localization imaging, in vitro bone marrow immortalization assay, in vivo mouse transplantation AML model, ChIP or chromatin binding assay for HOX cluster, pharmacological inhibition with selinexor and menin inhibitor Leukemia High 39443736
2024 CCDC28A is highly expressed in testes and is required for male fertility in mice: Ccdc28a knockout mice show 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 physically interacts with SPACA1 (sperm acrosome membrane-associated protein 1) and GSK3A (glycogen synthase kinase 3a), proteins whose deficiency in mice produces analogous bent-head and abnormal acrosome phenotypes respectively. 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 (whereas its paralog CCDC28B is expressed in somatic supporting cells). CCDC28A deficiency in knockout mice results in diminished sperm motility and structural disruption of the head-tail coupling apparatus (HTCA), specifically at the capitulum-basal plate junction, causing bending of the sperm head at the neck region and thickening of the tail midpiece, establishing CCDC28A as essential for HTCA formation and sperm tail morphogenesis. Knockout mouse model, histological analysis, transmission electron microscopy of sperm ultrastructure Scientific reports High 39500989
2021 NPM1::CCDC28A fusion was detected and characterized in AML samples. Functional studies demonstrated that the NPM1::CCDC28A fusion protein harbors an efficient nuclear export signal (NES) — either newly created or present in the CCDC28A partner — that drives cytoplasmic accumulation of the NPM1 fusion protein, supporting cytoplasmic relocation of NPM1 as critical for leukemogenesis. RNA sequencing, cytogenetic/FISH screening, immunohistochemistry for NPM1 localization, functional NES analysis Blood Medium 34343258
2005 A novel chromosomal translocation t(6;11)(q24.1;p15.5) in acute megakaryoblastic leukemia creates a NUP98-C6orf80 (CCDC28A) fusion gene, identified by molecular cytogenetics and RT-PCR, establishing CCDC28A as a fusion partner of NUP98. FISH, RT-PCR with NUP98 forward and CCDC28A (C6orf80) reverse primers Genes, chromosomes & cancer Medium 16028218

Source papers

Stage 0 corpus · 15 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 106 16467868
2019 Transcriptome analysis offers a comprehensive illustration of the genetic background of pediatric acute myeloid leukemia. Blood advances 73 31648321
2018 The genetics and clinical characteristics of children morphologically diagnosed as acute promyelocytic leukemia. Leukemia 57 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 16 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 10 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 5 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
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