Acute myeloid leukemia with DEK::NUP214 fusion resembling acute promyelocytic leukemia,initially presenting as sweet syndrome: A case report and literature review

Abstract

Some subtypes of acute myeloid leukemia share morphologic, immunophenotypic, and clinical features of acute promyelocytic leukemia but lack a promyelocytic leukemia–retinoic acid receptor alpha fusion gene. Herein, we present a case of acute myeloid leukemia with morphological and clinical features resembling those of acute promyelocytic leukemia, carrying the rare DEK::NUP214 fusion gene and presenting with sweet syndrome as the initial manifestation. In our case, the patient with acute myeloid leukemia carrying DEK::NUP214 fusion exhibited highly active bone marrow proliferation, with increased basophil and promyelocyte counts. To the best of our knowledge, this is the first reported case of acute promyelocytic leukemia–like acute myeloid leukemia carrying DEK::NUP214 fusion.

Introduction

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) characterized by abnormal accumulation of promyelocytes in the bone marrow (BM) and coagulation abnormality. The majority of cases possess a promyelocytic leukemia–retinoic acid receptor alpha (PML–RARA) fusion gene formed via a t(15;17) translocation. However, some AML cases resembling APL possess a negative PML–RARA fusion gene but exhibit a proliferation of hypergranular promyelocytes. Herein, we report a case of APL-like AML with sweet syndrome (SS) as the initial presentation, carrying the rare DEK::NUP214 fusion gene formed via a t(6;9)(p23;q34.1) translocation. DEK encodes a nuclear phosphoprotein involved in chromatin remodeling and transcription regulation, whereas NUP214 is a component of the nuclear pore complex that facilitates nucleocytoplasmic transport. The fusion gene disrupts normal cellular functions by enhancing protein synthesis specifically in myeloid cells, primarily through increased phosphorylation of the translation initiation factor eIF4E, leading to heightened translational activity without affecting transcription levels. Additionally, SS is a rare inflammatory disease characterized by sudden onset of fever and tender erythematous skin lesions, commonly localized on the face, neck, upper trunk, and limbs. ¹

Case report

The patient was an 18-year-old female of Han nationality who presented with a 3-day history of fever up to 39°C, accompanied with cough and scanty sputum. She was admitted to the emergency department of Qingdao Municipal Hospital on 4 May 2024. The patient had a history of nodular erythema for over half a year. Physical examination revealed abundant pigmented plaques on all four limbs, scattered erythematous nodules with tenderness on the right upper limb and both lower limbs, and elevated skin temperature. No lymphadenopathy or hepatosplenomegaly was observed, and there was no involvement of the central nervous system. Laboratory tests revealed a leucocyte count of 22.35 × 10⁹/L with 91.8% neutrophils, 4.5% lymphocytes, 0.30% eosinophils, and 3.20% monocytes. Furthermore, the neutrophil count was 20.54 × 10⁹/L, the lymphocyte count was 1 × 10⁹/L, the platelet count was 128 × 10⁹/L, and the hemoglobin level was 92 g/L. Fibrinogen and D-dimer levels were 4.7 g/L and 1.87 μg/mL, respectively. The levels of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were elevated.

The patient’s infection markers were elevated, primarily evidenced by increased white blood cell counts, CRP levels, ESR levels, and procalcitonin levels. Based on these findings, a preliminary diagnosis of skin and soft tissue infection was made. Piperacillin–tazobactam and propacetamol were administered to treat the infection. Two days later, the erythematous nodules on the patient’s right upper limb and both lower limbs progressed into blisters of varying sizes, with diameters approximately ranging from 1 to 5 cm (Figure 1(a)). Skin biopsy showed a significant infiltration of neutrophils in the subcutaneous fat (Figure 1(b) and (c)), suggesting SS or pyoderma gangrenosum. Nonsteroidal anti-inflammatory drugs and antibiotics were discontinued and treatment with methylprednisolone (60 mg intravenously for 5 days) was initiated.

Figure 1.

Clinicopathological features of sweet syndrome in our patient: (a) Nodular skin lesions localized on the left lower leg, with a diameter of approximately 1 cm. (b) (c) Skin biopsy showed significant infiltration of neutrophils in the subcutaneous fat. ((b): high power view, 400× magnification and (c): low power view, 100× magnification).

On the 4th day of admission, the patient still had recurrent high fever and began to develop chills, significant fatigue, and nausea with vomiting. The white blood cell count increased to 35.1 × 10⁹/L, and fibrinogen and D-dimer levels increased to 5.7 g/L and 2.04 μg/mL, respectively. Immature cells were observed in the peripheral blood classification. Blood cultures showed no bacterial growth, and the results of Mycobacterium tuberculosis gamma interferon test were negative. The BM smear showed extremely active granulocytic proliferation, with primitive granulocytes accounting for 15% of all nucleated cells and promyelocytes accounting for 47% of all nucleated cells (Figure 2(a)). Cytochemical staining showed peroxidase positivity, periodic acid–Schiff positivity, naphthol AS-D chloroacetate esterase positivity, naphthol AS-D chloroacetate esterase inhibition, nonspecific esterase negativity, and acid-serum dehydrogenase cation esterase positivity, and immunohistochemistry showed weak positivity for CD117, MPO+, and lysozyme+ and negativity for CD34. Flow cytometry analysis revealed that myeloid blast cells accounted for 13.41% of the total nucleated cells in the bone marrow, expressing CD117, CD13, CD33, and CD38, with partial expression of CD64, CD34, and cytoplasmic myeloperoxidase and no expression of HLA-DR. The results of chromosomal analysis were as follows (Figure 2(b)): 46, XX, t(6;9)(p23;q34.1). Mutations in NRAS (p.G13D, p.G13R, and p.G12D mutations), KRAS (p.G12V and p.G12D mutations), and PTPN11 (p.A72V mutation) were detected via targeted next-generation sequencing. Reverse transcription polymerase chain reaction screening assay for 43 leukemia fusion genes revealed the presence of DEK::NUP214 fusion. The diagnosis of this patient was APL-like AML with SS as the initial presentation, and fusion genes revealed the presence of DEK::NUP214.

Figure 2.

Bone marrow (BM) sample morphology and chromosomal karyotype analysis. (a) Promyelocytes with hypergranulated cytoplasm and invaginated nuclei (Wright–Giemsa-stained BM smear, 1000× magnification) and (b) G-banded karyotype showing 46, XX (all 20 karyotyped cells exhibited the same chromosomal abnormality, t(6;9)(p23;q34.1)).

The IVA chemotherapy protocol (idarubicin (16 mg, d1–3); cytarabine (100 mg, q12h d1–6); and venetoclax (100 mg, d5; 200 mg, d6; 400 mg, d7; 100 mg, d8–11)) was initiated on 11 May 2024. During the BM suppression period following chemotherapy, severe pulmonary infection, hypovolemic shock, respiratory failure, and other serious complications occurred. After symptomatic treatments such as fluid replacement, blood transfusion, noninvasive ventilatory support, and anti-infection therapy, the symptoms gradually improved. After the completion of treatment, the patient’s BM smear showed a decrease in blast count to 3%, achieving morphological complete remission. However, the patient did not achieve complete remission according to the response criteria of the International Working Group.^2,3 The second cycle of chemotherapy was then initiated using the VAC regimen, which includes venetoclax (100 mg, d1; 200 mg, d2; 400 mg, d3–14), azacitidine (110 mg, d1–7), and cytarabine (20 mg, d2–7). In the second chemotherapy cycle, multiple vesicular lesions on the limbs had crusted over. After the completion of treatment, the patient’s neutrophil count (0.56 × 10⁹/L) and platelet count (188 × 10⁹/L) partially recovered, meeting the criteria for complete remission with partial hematological recovery. ³ The patient was subsequently discharged and decided not to continue further treatment. However, during follow-up, we learned that the patient is scheduled to undergo allogeneic hematopoietic stem cell transplantation (allo-HSCT) at a higher-level hospital.

Discussion

AML with DEK::NUP214 fusion is a recurrent genetic abnormality primarily found in young adults (median age: 35 years) or patients with childhood AML (median age: 13 years). ⁴ Since 2008, AML associated with t(6;9)/DEK::NUP214 has been recognized as a distinct entity in the World Health Organization classification. ⁵ This translocation results in the fusion of DEK on chromosome 6 with NUP214 (also known as CAN) on chromosome 9. The resulting nucleoporin fusion protein acts as an aberrant transcription factor and alters nuclear transport by binding to soluble transport factors. This indicates that t(6;9)/DEK::NUP214 is a major driving factor in the pathogenesis of this condition. ⁶

Previous studies have shown that AML with t(6;9)/DEK::NUP214 is morphologically and immunophenotypically similar to AML with maturation or acute myelomonocytic leukemia.^7,8 BM morphology is frequently accompanied with increased levels of basophils, with Auer rods and fine particles observed in certain blast cells. These neoplasms are also typically characterized by a high frequency of FLT3 mutations, substantial chemotherapy resistance, and a very poor prognosis. A notable feature of this case is the increase in BM basophil count, which may be a morphologic hint for the presence of t(6;9)/DEK::NUP214. Interestingly, our case also showed a considerable increase in the proportion of promyelocytes with increased cytoplasmic granules, which has not been previously reported in cases of AML with DEK::NUP214 fusion; this condition is easily misdiagnosed as APL. Additionally, molecular screening identified mutations in genes known to have prognostic significance in AML, including NRAS, KRAS, and PTPN11. Visconte et al. suggested that the presence of single or multiple somatic mutations is an important factor influencing the clinical outcomes of patients with AML and t(6;9)/DEK::NUP214. ⁹ Mutations in NRAS and KRAS can lead to the continuous activation of RAS proteins and contribute to tumorigenesis. Studies have shown that patients with AML carrying RAS mutant genes may benefit from consolidation therapy with high-dose cytarabine after remission. ¹⁰ In addition, PTPN11 mutations were associated with lower complete remission rates and shorter overall survival in patients with AML. ¹¹ In summary, although DEK::NUP214 fusion and associated mutations may contribute to the overall prognosis, the patient’s partial hematological recovery after the second chemotherapy cycle reflects some level of therapeutic efficacy. However, these chromosomal and genetic factors likely play a role in the limited efficacy observed, and the patient will require further monitoring and potentially more aggressive treatment, including consideration for allo-HSCT, as the next step in her management.

This case fulfilled both major and minor criteria according to Von den Driesch modified criteria for SS. ¹² Malignancy-associated SS (MASS) accounts for approximately 15%–20% of all SS cases that can portend or co-occur with the malignancy. ¹³ Kazmi et al. ¹⁴ reported that SS occurred in 21 (1%) of the 2178 adult patients with AML; most of them were women, two-thirds of the patients presented with fever, and only one of the 21 patients with SS presented to the hospital prior to the diagnosis of AML, similar to our patient. Risk factors for MASS in patients with AML include the presence of FLT3 mutations and AML with myelodysplasia-related features. The median overall survival of patients with AML and SS did not significantly differ from that of patients with AML but no SS. Our case was a girl who presented with fever, thrombocytopenia, and anemia, but molecular testing did not detect any FLT3 mutations. Systemic corticosteroids are the first-line treatment for SS. Therefore, we initiated methylprednisolone therapy early in the disease course. However, in cases of MASS, prompt and effective initiation of antileukemic therapy is also important.

In summary, in our patient with AML, DEK::NUP214 fusion was accompanied with SS. It masquerades as an infection in the early stages, and the increased promyelocyte count in the BM can easily lead to misdiagnosis as APL. Based on the cases reported by Slovak et al., ⁸ the 5-year survival rate is approximately 28% for children and approximately 9% for adults. Therefore, when a child presents with typical cutaneous manifestations of SS, physicians should maintain a high degree of suspicion to search for underlying malignancies and systemic diseases and initiate corticosteroid and leukemia treatments as early as possible. The available evidence suggests that active treatments such as allo-HSCT may improve survival rates. ⁶ These findings warrant further research.