Myeloid blast phase of chronic myeloid leukemia with co-occurring t(11;12)(p15;q13)/NUP98::HOXC12: a novel NUP98 fusion partner

NUP98 on 11p15.4 encodes nucleoporin 98 protein that is involved in nuclear-cytoplasmic trafficking, chromatin remodeling, and transcriptional regulation. NUP98 translocations are predominantly linked to myeloid malignancies, most often acute myeloid leukemia (AML), and encompass more than 30 fusion partners, most commonly, NSD1 (at 5q35.3) and HOXA9 (at 7p15.2) in adult case studies.^1-4 Rarely, NUP98 fusions occur in chronic myeloid leukemia (CML) patients who underwent myeloid blast crisis, with identified fusion partners of HOXA9, DDX10, PMX1, and PSIP1 (LEDGF).^2,5,6

Here, we report a CML case in myeloid blast phase (BP) in a poorly managed patient with acquisition of NUP98 rearrangement (NUP98-R). The patient was a 58-year-old man with a 4-year history of CML, chronic-phase, diagnosed on a bone marrow biopsy in June 2020. Conventional karyotyping was performed at diagnosis and showed no additional cytogenetic abnormalities. He had been treated initially with imatinib followed by bosutinib and dasatinib but these medications were intermittently discontinued due to side effects, non-compliance, and/or an insurance issue, and he was off medication for 3 months before presentation. In November 2024, the patient sought medical attention for extreme fatigue and dyspnea. At presentation, his complete blood count showed leukocytosis (17.2×10⁹/L), anemia (9.0 g/dL), and marked thrombocytopenia (26×10⁹/L) along with 56% circulating blasts (Figure 1A, B). Bone marrow aspiration and biopsy showed hypercellular (>95%) marrow with left-shifted granulopoiesis and 35% blasts on aspirate smears (Figure 1C-E). Flow cytometric immunophenotyping showed the blasts had a myeloid immunophenotype, positive for CD13, CD45 (dim), CD117 (increased), CD123 (increased), HLA-DR (decreased to absent), and myeloperoxidase, without co-expression of CD33, CD34, TdT, T-cell, B-cell, or additional monocytic markers (Figure 1F). Chromosomal analysis revealed an abnormal karyotype: 46,XY,t(9;22)(q34;q11.2),t(11;12)(p15;q13) [20] (Figure 2A). Fluorescence in situ hybridization (FISH) showed that the concurrent t(11;12)(p15;q13) resulted in NUP98-R in 92% of the interphase cells analyzed using a break-apart probe (Figure 2B). Real-time reverse transcription polymerase chain reaction (RT-PCR) confirmed a b2a2 fusion transcript encoding a p210 isoform. RNA-sequencing analysis detected a NUP98::HOXC12 in-frame fusion transcript consisting of NUP98 (exons 1-12) on chromosome 11 and HOXC12 (exon 2) containing intact Homeobox (HOX) domain on chromosome 12, confirmed by RT-PCR followed by Sanger sequencing (Figure 2C). No somatic mutations including FLT3 and WT1 were detected by next generation sequencing analysis. No mutations in the ABL1 kinase domain were identified. A diagnosis of myeloid blast phase of CML, with NUP98-R, was rendered.

Figure 1.Morphological and immunophenotypic features. (A, B) Peripheral blood smear shows mild leukocytosis and increased circulating blasts (Wright-Giemsa; A, 400x; B, 1,000x), (C, D) Bone marrow trephine biopsy specimen shows a hypercellular marrow (~ 100%) with increased immature myeloid cells and blasts (hematoxylin-eosin; C, 40x; D, 500x). (E) Bone marrow aspirate smears show increased blasts (Wright-Giemsa, 1,000x). (F) Flow cytometric immunophenotyping showed that the myeloblasts express CD13 (major subset), CD45 (dim), CD117 (increased), CD123 (increased), HLA-DR (variably decreased to absent), and myeloperoxidase (MPO, subset) without co-expression of CD33, CD34, or TdT.

Given his extensive cardiovascular co-morbidities, the patient was treated initially with decitabine, venetoclax, and bosutinib. He also received prophylactic intrathecal chemotherapy with four doses of cytarabine. A follow-up bone marrow specimen on day 32 after one cycle of induction was 20-40% cellular with no increase in blasts by morphology and rare CD117⁺ immature cells by immunohistochemistry. However, FISH analysis showed persistent BCR::ABL1 and NUP98-R in 55.5% and 48% of analyzed cells, respectively, including in segmented neutrophils.

Figure 2.Cytogenetic and molecular characteristics. (A) Chromosomal analysis demonstrates an abnormal karyotype with co-occurring balanced t(9;22)(q34;q11.2) (blue arrows) and t(11;12)(p15;q13) (purple arrows). (B) Fluorescence in situ hybridization (FISH) analysis with a break-apart probe (BAP) for NUP98 (top) shows a signal pattern of 1R1G1F, confirming NUP98 rearrangement; the FISH analysis with an extra signal dual color BCR::ABL1 probe (ES DC, bottom) shows a signal pattern of 2R1G1F, indicating the presence of major BCR::ABL1 fusion product, corresponding to a p210 isoform. Both fusion products are detected in both round (blasts) and segmented (neutrophils) cells. (C) RNA sequencing detected a NUP98::HOXC12 in-frame fusion transcript consisting of NUP98 (exons 1-12) from chromosome 11p15 and HOXC12 (exon 2) from 12q13.

He was then transferred to local care due to the lack of insurance coverage in our system and lost to follow-up in our system thereafter.

Blast crisis (BP) of CML is associated with acquisition of additional chromosomal aberrations, gene mutations, decreased telomere activity, and epigenetic modifications.⁷ NUP98 rearrangement was one of the newly introduced leukemia-defining genetic aberrations in the 5^th edition of the World Health Organization (WHO) Classification and International Consensus Classification (ICC) of myeloid neoplasms.^8,9 NUP98 fusions typically deregulate expression of HOX cluster genes in leukemogenesis, and are associated with treatment failure, high relapse rates, and poor prognosis.¹⁰ Although uncommon, acquisition of NUP98-R in CML has been reported to associate with myeloid blast crisis in several case reports that show variable morphologic and phenotypic features.^2,5,6 NUP98 fusions with HOXC partners in CML progression have not been previously documented. Homeodomain-containing HOX genes constitute one essential category of NUP98 fusion partners and are composed of four gene clusters on chromosomes 7p15.2 (HOXA), 17q21.3 (HOXB), 12q13.3 (HOXC) and 2q21 (HOXD). To date, at least ten HOX clustered genes (HOXA6, HOXA9, HOXA11, HOXA13, HOXC11, HOXC13, HOXD8, HOXD11, HOXD12, and HOXD13) have been implicated in AML carrying NUP98-R.^1-3 Among these HOX genes, HOXA9 was the first identified fusion partner for NUP98-R and the second most frequently detected NUP98 fusion partner in adult AML.^1-3 In all instances, the C-terminal DNA-binding homeodomain of the HOX protein is retained in the fusion protein, and the transactivation domain is replaced by the FG and GLFG repeats of NUP98. Although most NUP98-R AML cases lack a consistent leukemic phenotype, specific fusion partner protein shows a preferential association with a particular leukemia subtype. For example, AML with NUP98::RARG showed features resembling acute promyelocytic leukemia.¹¹ A fusion partner at 12q13 in CML-BP has not been previously reported, and in cases of AML, reported fusion genes include the partners HOXC11, HOXC13, and RARG.^2,10 Here, we present a CML-BP case with acquisition of NUP98-R involving a novel partner gene HOXC12 on 12q13, and with an unique immunophenotype that was CD34^– CD117⁺ differentiating towards basophilic lineage.

Notably, this case also illustrates the first-time observation of concurrent NUP98 and BCR::ABL1 translocations in both blasts and segmented neutrophils at diagnosis and after induction with resolution of BP. The detection of NUP98-R in neutrophils is unusual and may suggest either early acquisition of the fusion during CML evolution, or an unexpected biological behavior of NUP98::HOXC12 fusion in perturbing myeloid proliferation and/or differentiation. A similar observation was noted in a recent study on longitudinal clonal evolution for adult AML with NUP98-R, in which seven of 12 patients were found to have more NUP98-rearranged cells than blast counts in follow-up samples, raising the possibility of a subset of maturing myeloid cells carrying NUP98-R.¹² Mechanistically, ectopic overexpression of NUP98::HOXA9 delivered through retroviral or lentiviral transduction was previously demonstrated to be capable of enhancing myeloid cell proliferation in colony-forming assays,^13,14 inducing myeloproliferative disease in murine models,¹³ and promoting CML progression in genetically engineered CML models.¹⁴ In these disease models, enforced overproduction of NUP98::HOXA9 led to sustained upregulation of downstream transcripts including genes in the HOXA and HOXB clusters and their co-factors such as MEIS1 and PBX3, while the leukemic transformation required co-expression or recruitment of cofactors such as KMT2A or MEIS1 following a latency period.^13,14

HOXC12 has not been previously associated with hematologic malignancies. It belongs to the DNA-binding HOX gene family encoding hematopoietic transcription factors essential for promoting myeloid proliferation and/or differentiation. HOXC12 represents one of the HOXC cluster genes on chromosome 12q13, with neighboring HOXC11 and HOXC13 genes. HOXC12 in fusion with NUP98 would likely derive from alternative splicing at intronic sites in response to HOX pathway deregulation. The identification of a novel HOXC family partner gene has biological and therapeutic impact, as the immunophenotype, transcriptome, and epigenome of HOX-activating fusion partners may offer targets for more effective therapies. Specifically, NUP98 fusion protein interactions such as HOXA/ MEIS1 axis are vulnerable to menin inhibitors, offering an alternative therapeutic approach currently undergoing phase I clinical trial. Menin serves as the scaffold protein to interact with KMT2A and menin-KMT2A association is required for maintenance of HOXA/MEIS1 upregulation, the critical leukemic transcription program in AML with NUP98-R and others. Although HOXC members share conserved sequence homology to HOXA genes, they exhibit distinct biological divergence in leukemogenesis with limited available studies on HOXC genes, such as less MEIS1 dependent, involvement of long non-coding RNA like HOTAIR within the HOXC cluster in epigenetic regulation and oncogenic activation, and promoting leukemic cell survival and proliferation.¹⁵ The prognostic relevance of NUP98-R in CML is unknown but appears to have conferred imatinib resistance and contributed to leukemogenesis in one study with a DDX10 fusion partner and a latency period of 4 months.⁶ It remains unclear when NUP98::HOXC12 emerged in this case, whether the resultant fusion confers resistance to tyrosine kinase inhibitors, and how NUP98::HOXC12 facilitates clonal evolution and leukemic transformation of CML.

In summary, we present an unusual CML-BP case with a poorly controlled disease course and acquisition of NUP98-R involving a novel partner HOXC12 at 12q13, which has not been previously associated with hematologic malignancies.

This case broadens the spectrum of HOX fusion partner genes in NUP98 translocations and underscores the complex biology underlying the clonal evolution of CML progression. Further studies are needed to better understand the structural and functional properties of NUP98 fusion oncoproteins and partner-specific co-factors at a higher resolution level than ever before. We acknowledge the limitation of this single case study and the lack of single cell dissection of clonal architecture in the progressive course of CML.

This study was approved by the Institutional Review Board at the MD Anderson Cancer Center (2025-0535).

Footnotes

• Received December 23, 2026
• Accepted April 21, 2026

Correspondence

L. QIU - lqiu@mdanderson.org

Disclosures

No conflicts of interest to disclose.

Contributions

Acknowledgments

We would like to thank Mr. Roland Delgado and Mr. Su Yang from the Clinical Cytogenetics Laboratory for their assistance with FISH imaging and analysis.