CCDC88C::PDGFRB-rearranged myeloid neoplasm with predominant neutrophilia and rapid response to imatinib: a molecularly defined case report

Abstract

Myeloid/lymphoid neoplasms with PDGFRB rearrangements are rare hematologic malignancies usually associated with eosinophilia and sensitivity to tyrosine kinase inhibitors, whereas atypical presentations remain poorly defined. We report a 60-year-old man with persistent leukocytosis and thrombocytopenia detected during a routine health examination. Bone marrow examination revealed marked granulocytic proliferation without increased blasts, and peripheral blood showed predominant neutrophilia with only mild eosinophilia. Cytogenetic analysis identified a t(5;14) translocation. RNA sequencing detected an in-frame CCDC88C exon 12::PDGFRB exon 11 fusion, and targeted sequencing additionally identified an ATM frameshift mutation. Treatment with low-dose imatinib (200 mg daily) led to rapid normalization of leukocyte counts within one week and sustained hematologic remission during follow-up. This case broadens the clinicopathologic spectrum of CCDC88C::PDGFRB-rearranged neoplasms and highlights the value of RNA sequencing in identifying actionable kinase fusions in atypical myeloproliferative presentations.

Introduction

Myeloid/lymphoid neoplasms with eosinophilia and rearrangements of platelet-derived growth factor receptor beta (PDGFRB) represent a distinct group of hematologic malignancies characterized by constitutive activation of tyrosine kinase signaling. These neoplasms are generally linked to eosinophilia and exhibit a high level of sensitivity to tyrosine kinase inhibitors such as imatinib. However, mounting evidence indicates considerable heterogeneity in their clinical presentation (1, 2).

To date, numerous PDGFRB fusion partners have been identified, contributing to aberrant activation of downstream signaling pathways (3, 4). However, the majority of reported cases remain limited to isolated case reports, and rare fusion partners continue to be identified (5–7). The clinical manifestations of this condition can vary widely, and atypical presentations without prominent eosinophilia may lead to diagnostic challenges. Among these rare fusion partners, CCDC88C has only rarely been reported in PDGFRB-rearranged myeloid neoplasms, and the associated clinicopathologic spectrum remains poorly defined.

In this study, we present a rare case of a PDGFRB-rearranged myeloid neoplasm that harbours a CCDC88C::PDGFRB fusion, as detected by RNA sequencing. The patient had predominant neutrophilia, mild eosinophilia, and thrombocytopenia, but remained clinically asymptomatic. In addition, a concurrent ATM frameshift mutation was detected, raising the possibility of additional molecular complexity. The patient showed a rapid hematologic response to imatinib therapy, underscoring the significance of molecular diagnosis in directing treatment.

Case presentation

A 60-year-old male patient was admitted to our hospital after abnormal blood cell counts were detected during a routine health examination. The patient exhibited no symptoms, including fever, fatigue, or weight loss. Preliminary laboratory findings on December 18, 2025 revealed a total leukocyte count of 24.92×10^9/L, a neutrophil count of 21.41×10^9/L, an eosinophil count of 0.72×10^9/L, a basophil count of 1.24×10^9/L (5% on manual differential), a hemoglobin level of 164 g/L, and a platelet count of 77*10^9/L. Peripheral blood smear analysis revealed a predominance of mature neutrophils with a left shift (manual differential: band forms 23%, segmented neutrophils 56%, metamyelocytes 2%, promyelocytes 1%, lymphocytes 6%, monocytes 1%, eosinophils 6%, basophils 5%). Serum lactate dehydrogenase was mildly elevated at 240 U/L (reference <250 U/L). On January 21, 2026, the WBC count peaked at 32.21×10^9/L, accompanied by mild to moderate eosinophilia (up to 1.93×10^9/L) and basophilia (1.93×10^9/L).

Physical examination revealed no palpable splenomegaly. However, abdominal ultrasonography showed mild splenic enlargement, with a thickness of 4.1 cm.

Bone marrow aspirate smears were of good quality and showed extremely active proliferation. Granulopoiesis was markedly increased (88.5%), whereas erythropoiesis was relatively decreased (6.5%), with a G/E ratio of 13.62:1. The proportion of neutrophilic myelocytes and metamyelocytes was increased, with coarse and increased cytoplasmic granules. Erythroid cells were reduced in proportion, without obvious morphologic abnormalities in mature erythrocytes. Lymphocytes were decreased in proportion, and monocytes were within the normal range. A total of 102 megakaryocytes were observed, but platelet-producing megakaryocytes were rare, and platelets were only occasionally seen. No increase in blast cells was identified (0%). Bone marrow and peripheral blood morphology are shown in Figure 1. Conventional flow cytometry did not reveal any aberrant immunophenotype.

Figure 1.

Morphology of bone marrow and peripheral blood. (A) Bone marrow smear, low-power magnification (×100) showing markedly hypercellular bone marrow with extensive granulocytic proliferation. (B) Bone marrow smear, high-power magnification (×1000, oil immersion) demonstrating predominant neutrophilic granulopoiesis with increased myelocytes and metamyelocytes; no increase in blast cells is observed. (C) Peripheral blood smear, high-power magnification (×1000, oil immersion) showing marked neutrophilia with left shift; eosinophils are only occasionally seen.

Conventional G-banding karyotyping was performed on unstimulated bone marrow cells after 24-hour culture (banding resolution 200–300). The result was 46,XY,t(5;14)(q31;q24) (20), with all 20 metaphases showing the same translocation and no additional clonal abnormalities detected (Supplementary Figure 1). FISH with PDGFRB break-apart probes was not performed.

Whole transcriptome RNA sequencing was performed on bone marrow RNA using ribosomal RNA depletion (RiboZero) library preparation and the Illumina NovaSeq 6000 platform. Fusion genes were detected using the STAR-Fusion pipeline with the hg19 reference genome. RNA sequencing identified an in-frame CCDC88C exon 12::PDGFRB exon 11 fusion (hg19: chr14:91791123 to chr5:149506177), supported by 72 junction reads and 6 spanning reads (Figure 2). The fusion retained the C-terminal tyrosine kinase domain of PDGFRB (7, 8).

Figure 2.

Schematic representation of the CCDC88C::PDGFRB fusion identified by RNA sequencing. The fusion involves exon 12 of CCDC88C and exon 11 of PDGFRB, resulting from a t(5;14)(q32;q32) translocation (at nucleotide resolution). The chimeric protein retains the N-terminal coiled-coil domain of CCDC88C and the C-terminal tyrosine kinase domain of PDGFRB, leading to constitutive kinase activation.

Whole exome sequencing (WES) and low-depth whole genome copy number sequencing (CNV-seq) were performed for additional molecular characterization. WES covered >20,000 protein-coding genes and flanking regions at a mean depth exceeding 2000×, detecting single nucleotide variants and small insertions/deletions. CNV-seq covered all autosomes and sex chromosomes, capable of detecting chromosomal aneuploidies and copy number alterations ≥100 kb. No additional chromosomal abnormalities were identified beyond the known t(5;14) translocation. WES detected a heterozygous ATM frameshift mutation, c.1381del (p.Glu461LysfsTer12), with a variant allele frequency of 35.7%, classified as likely pathogenic by ACMG criteria. Germline origin was not formally confirmed by testing non-hematopoietic tissue. No pathogenic or likely pathogenic variants were identified in CSF3R, consistent with a pure PDGFRB-rearranged neoplasm. Based on these findings, a diagnosis of PDGFRB-rearranged myeloid neoplasm was established. Imatinib was initiated at 200 mg once daily on January 23, 2026. This dose was selected based on evidence that low-dose imatinib (100–200 mg/day) is sufficient for sustained remission in PDGFRB-rearranged neoplasms (9, 11). Jawhar et al. (9) reported that 7 of 22 patients with PDGFRB-rearranged myeloid/lymphoid neoplasms achieved complete molecular remission on 100 mg/day, and Barbato et al. (7) similarly used 200 mg/day with complete molecular remission in a PDGFRB::CCDC88C-rearranged case.

A rapid hematologic response was observed, with the WBC count decreasing to 7.61 × 10^9/L by January 30, 2026, and further normalizing to 6.10 × 10^9/L by February 6, 2026. Platelet counts gradually recovered, and eosinophil levels normalized. As of the last follow-up on May 27, 2026, blood counts remained normal, indicating durable hematologic remission lasting approximately 4 months. The dynamic changes in hematologic parameters are shown in Figure 3.

Figure 3.

Hematologic parameters and clinical timeline. (A) WBC and ANC. (B) Eosinophil and basophil counts. (C) Platelet count and hemoglobin (dual-axis). (D) Clinical timeline. The orange dashed line indicates imatinib initiation (200 mg/day).

Discussion

Myeloid/lymphoid neoplasms with PDGFRB rearrangements are characterized by constitutive activation of tyrosine kinase signaling and are typically associated with eosinophilia and sensitivity to imatinib (1, 3). Nevertheless, clinical heterogeneity is increasingly recognized, and atypical cases without prominent eosinophilia may pose diagnostic challenges.

In this case, a rare CCDC88C::PDGFRB fusion was identified. Only a limited number of such cases have been reported, highlighting the rarity of this fusion partner (6, 7). Similar to previously published cases, the fusion in our patient was associated with sensitivity to imatinib. Compared with earlier reports, however, our patient was notable for an asymptomatic presentation with predominant neutrophilia and only mild eosinophilia, further broadening the clinical spectrum of PDGFRB-rearranged neoplasms (5, 7).

The oncogenic mechanism of PDGFRB fusion proteins is primarily driven by constitutive activation of the kinase domain. In most cases, the 5′ fusion partner provides an oligomerization domain, enabling ligand-independent receptor dimerization and activation (1, 3, 7). CCDC88C encodes a coiled-coil domain-containing protein involved in cytoskeletal organization and Wnt signaling regulation. The presence of oligomerization-related domains in CCDC88C may facilitate constitutive activation of PDGFRB kinase signaling. Activated PDGFRB signaling can trigger multiple downstream pathways, including STAT5, PI3K/AKT, and MAPK pathways, thereby promoting proliferation and survival of myeloid cells (1, 3).

A notable feature of this case was not the complete absence of eosinophilia, but rather its mild nature. Although eosinophilia is a common feature of PDGFRB-rearranged neoplasms, it is not universal (1, 2). The predominance of neutrophilia in our patient suggests that additional molecular or lineage-specific factors may influence phenotypic heterogeneity. Such atypical presentations may lead to misdiagnosis as other myeloproliferative neoplasms, emphasizing the importance of comprehensive molecular testing.

The rapid hematologic response to low-dose imatinib strongly supports the pathogenic role of the fusion. PDGFRB-driven neoplasms are highly sensitive to tyrosine kinase inhibition, and early molecular identification of such fusions is therefore critical for guiding targeted therapy (1, 7).

A concurrent ATM frameshift mutation was also identified. Although ATM is a key regulator of the DNA damage response and genomic stability, its role in PDGFRB-rearranged neoplasms remains unclear. In this context, the ATM variant detected in this case warrants cautious interpretation. With a VAF of 35.7% and no confirmation from non-hematopoietic tissue, its origin remains uncertain—it could be somatic, germline, or mosaic. The patient had no personal or family history suggestive of ataxia-telangiectasia. Whether this variant contributes to the disease phenotype is unknown (10).

Importantly, this case highlights the diagnostic value of RNA sequencing in detecting rare gene fusions. Notably, the karyotypic localization of the 14q breakpoint to band q24 differs from the molecular localization of CCDC88C at 14q32.11. This discrepancy reflects the inherent resolution limit of conventional G-banding (approximately 5–10 Mb at the 200–300 band level), rather than a biological inconsistency. RNA-seq maps breakpoints at nucleotide resolution and is the gold standard for fusion partner identification in this context. Conventional cytogenetics and morphology may be insufficient to identify actionable kinase fusions, whereas comprehensive molecular profiling enables precise diagnosis and personalized treatment (4). Molecular testing is also essential to distinguish PDGFRB-rearranged neoplasms from other BCR::ABL1-negative myeloproliferative neoplasms, as well as from cytogenetically similar but biologically distinct fusions that are not sensitive to tyrosine kinase inhibitors.

Six cases of CCDC88C::PDGFRB fusion (including one in the inverted PDGFRB::CCDC88C orientation) have been reported across five publications (Supplementary Table 1) (6–8, 11, 12). The breakpoints are heterogeneous, involving at least five different exon–exon junctions, and the associated diagnoses range from chronic myeloid/lymphoid neoplasms with eosinophilia to BCR::ABL1-like acute lymphoblastic leukemia. Imatinib was effective in every case, consistent with retention of the PDGFRB tyrosine kinase domain across all reported fusions. The present case differs from previously reported cases in three respects: a previously undescribed fusion breakpoint (CCDC88C exon 12 → PDGFRB exon 11), the oldest patient to date (60 years), and the first concurrent germline ATM pathogenic variant.

Limitations

Several limitations of this report should be acknowledged. First, FISH with PDGFRB break-apart probes and RT-PCR validation of the fusion transcript were not performed, though the combination of conventional karyotyping and RNA-seq provided sufficient evidence for diagnosis. Second, fusion transcript monitoring by RT-qPCR was not performed during follow-up; this would be valuable for assessing molecular response depth and guiding treatment duration, analogous to BCR::ABL1 monitoring in CML. Third, the follow-up duration is relatively short (approximately 4 months), and extended observation is needed to confirm the durability of remission and identify any potential late relapse or resistance. Finally, whether the germline ATM pathogenic variant contributed to the disease phenotype or carries prognostic significance remains uncertain.

Conclusions

This case expands the clinicopathologic spectrum of CCDC88C::PDGFRB-rearranged myeloid neoplasms by demonstrating that prominent eosinophilia is not required for diagnosis. Comprehensive molecular testing, particularly RNA sequencing, is essential in atypical myeloproliferative presentations, as timely identification of actionable kinase fusions can directly guide effective targeted therapy.

Funding Statement

The author(s) declared that financial support was received for this work and/or its publication. This work was supported by the Doctoral Seedling Project of the Second Affiliated Hospital of Fujian Medical University (grant number BS202403). The funder had no role in the study design, data collection, analysis, interpretation, manuscript writing, or the decision to submit for publication.

Data availability statement

The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.

Ethics statement

Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

Author contributions

YG: Conceptualization, Data curation, Investigation, Writing – original draft, Writing – review & editing. HW: Data curation, Investigation, Writing – review & editing. ZC: Data curation, Investigation, Writing – review & editing. GC: Data curation, Formal analysis, Investigation, Writing – review & editing. LM: Conceptualization, Supervision, Writing – review & editing. XG: Conceptualization, Supervision, Writing – review & editing.

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Generative AI statement

The author(s) declared that generative AI was not used in the creation of this manuscript.

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Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2026.1855322/full#supplementary-material