Rare Fusion Gene and WT1 Overexpression Define an Aggressive Leukemia Subtype

A rare and devastating case of leukemia has given researchers an unusually clear window into one of the most aggressive forms of blood cancer ever described. In a report published in Cancer Reports, clinicians in China documented a 57-year-old woman whose five-year history of myelodysplastic syndrome, a disorder in which the bone marrow produces defective blood cells, transformed into acute myeloid leukemia carrying two molecular abnormalities simultaneously: the DEK::CAN fusion gene and marked overexpression of the WT1 gene. According to the authors, this specific combination has never been reported before in a case of myelodysplastic syndrome-transformed acute myeloid leukemia, making the patient a singular point of reference for hematologists trying to understand how these genetic events interact to drive malignant transformation.

The DEK::CAN fusion gene arises from a balanced chromosomal translocation known as t(6;9)(p23;q34), in which segments of chromosomes 6 and 9 swap places and fuse the DEK gene to the CAN gene, also called NUP214. This fusion is found in only about 1 to 2 percent of all acute myeloid leukemia patients, but its presence carries serious consequences. The abnormal protein it produces disrupts nucleoporin function, impairing the carefully regulated transport of molecules between the nucleus and the cytoplasm and scrambling the signal transduction pathways that depend on that traffic. At the same time, the fusion constitutively activates the mTOR signaling pathway, a central growth-control circuit, pushing malignant cells to proliferate relentlessly while blocking the programmed cell death that would normally eliminate damaged cells.

WT1 tells a complementary story. Originally identified as a tumor suppressor in kidney cancer, the gene frequently behaves as an oncogene in blood malignancies, and its overexpression has been detected across myeloid neoplasms including both myelodysplastic syndromes and acute myeloid leukemia. When WT1 is overproduced, it suppresses pro-apoptotic genes such as BAX and aberrantly activates anti-apoptotic pathways including PI3K/AKT, tipping the delicate balance between cell survival and cell death in favor of the malignant clone. This dual action directly promotes the expansion of leukemic cells and fosters resistance to chemotherapy. The Chinese team reasoned that when DEK::CAN and WT1 overexpression occur together, the two abnormalities may synergize across multiple signaling pathways and transcriptional networks, producing a disease that is both highly aggressive and unusually tolerant of standard treatment.

The patient’s clinical course illustrates that synergy in stark terms. Admitted in August 2021 with three days of fatigue and dizziness after months of untreated cytopenia, she presented with profound pancytopenia: a white blood cell count of just 0.68 billion cells per liter, hemoglobin of 35 grams per liter, and platelets of 23 billion per liter. Bone marrow examination revealed a hypercellular marrow packed with 81 percent blasts showing monocytoid features, consistent with acute monocytic leukemia of the AML-M5 subtype. Both the granulocytic and erythroid lineages were severely suppressed, and dysplastic changes were visible across cell lineages, a hallmark of the disease’s myelodysplastic origins. Flow cytometric immunophenotyping confirmed a blast population expressing markers such as CD117, CD13, CD33, CD34, HLA-DR, and aberrant nTDT, while conventional G-banding karyotype analysis of twenty metaphase spreads revealed the telltale 46,XX,t(6;9)(p23;q34) karyotype.

Molecular testing then delivered the findings that set this case apart. A multiplex real-time reverse transcription PCR screening panel covering 56 leukemia-related fusion genes returned a positive result for DEK::CAN, which quantitative PCR verified at a DEK::CAN/ABL ratio of 188.21 percent, an extraordinarily high transcript burden. The same panel measured WT1 mRNA at a WT1/ABL ratio of 52.90 percent, far above the normal reference threshold of 2.5 percent, confirming overexpression. Targeted next-generation sequencing of 22 AML and MDS-related genes added a third layer of complexity: a non-synonymous mutation in exon 6 of the U2AF1 gene, c.467G>A resulting in the p.Arg156His substitution, detected at a variant frequency of 43.30 percent. Notably, no common mutations in FLT3, RAS, IDH2, DNMT3A, or TET2 were found, distinguishing this case from the typical mutational landscape of t(6;9) leukemia.

The U2AF1 mutation may be the key to understanding why this case was so aggressive. Recent research has shown that both DEK and WT1 physically interact with the U2AF1/U2AF2 heterodimer, the core spliceosome component that governs alternative splicing, the process by which RNA transcripts are cut and reassembled into different protein-coding forms. Both oncogenes can therefore influence the splicing of numerous genes involved in hematopoietic differentiation and chemotherapy resistance. Because the patient’s U2AF1 mutation alters the very protein that DEK and WT1 engage, the researchers suggest it may have enhanced or synergized with the fusion gene and WT1 overexpression in corrupting RNA splicing. Combined with HOX gene reprogramming, evasion of apoptosis, and chemotherapy tolerance, this triple hit could plausibly shape the exceptionally aggressive phenotype observed.

Treatment followed established guidelines for high-risk AML. Classified as high risk based on the t(6;9) karyotype and DEK::CAN positivity, the patient received two cycles of intensive induction chemotherapy with the IA regimen of idarubicin and cytarabine beginning in late August 2021. The first cycle failed to achieve remission, leaving bone marrow blasts at 25.5 percent, but the second cycle brought blasts down to 2 percent with normalized blood counts, achieving complete remission. Because acute monocytic leukemia carries a heightened risk of central nervous system relapse, she underwent lumbar puncture with intrathecal chemotherapy, followed by three cycles of intermediate-dose cytarabine consolidation. Along the way she endured a pulmonary fungal infection, Klebsiella pneumoniae sepsis, and Gram-negative bacterial sepsis, all controlled with anti-infective therapy, and experienced a transient period of remission with incomplete hematologic recovery before regaining full remission in February 2022.

Yet the marrow’s response told only half the story. After the third consolidation cycle, the patient developed severe myelosuppression with a platelet count plummeting to 19 billion per liter. In the early morning of February 22, 2022, she suddenly lost consciousness and was found with bloody vomitus; resuscitation failed and she died. Clinicians suspected fatal bleeding, possibly gastrointestinal, intracranial, or pulmonary, though no autopsy was performed to confirm the cause. Critically, the recurrent infections and cumulative chemotherapy toxicity had prevented her from ever undergoing allogeneic hematopoietic stem cell transplantation, the intervention that published data identify as the single most important determinant of survival in DEK::CAN-positive disease. Her marrow remained in morphologic remission at the time of her death, a dissociation between molecular response and clinical tolerability that the authors describe as the case’s most sobering lesson.

The literature reinforces that lesson with hard numbers. A multicenter study of 107 patients with t(6;9)/DEK-NUP214-positive myeloid neoplasms found that patients who received allogeneic transplantation had a median overall survival of 62 months and an estimated five-year survival of roughly 40 to 50 percent, while non-transplanted patients had a median survival of only 17 months and a five-year survival approaching zero. Chemotherapy alone, in other words, yields five-year survival of just 0 to 5 percent. The present patient’s approximately 12-month survival without transplantation falls squarely within that non-transplant experience. A separate molecular study of nine patients with isolated t(6;9) disease found that 83 percent carried at least one somatic mutation and reported a median overall survival of only 20 months, underscoring how uniformly poor the outlook remains for this cytogenetic subgroup.

The authors draw several practical conclusions from the case. All newly diagnosed myelodysplastic syndrome patients should routinely undergo karyotype analysis and DEK::CAN fusion gene screening, since the fusion’s presence fundamentally alters prognosis and treatment planning. Once any form of remission is achieved, whether complete remission or remission with incomplete hematologic recovery, transplantation should be bridged promptly under controlled infection and adequate organ function, without waiting for full blood count recovery. For patients rendered ineligible by toxicity, the case points toward emerging low-toxicity alternatives: preclinical studies show that mTOR inhibitors such as everolimus can suppress the growth of DEK::CAN-positive cells, and WT1-targeted immunotherapy is under development. Dynamic monitoring of WT1 levels before treatment, after chemotherapy, and around transplantation is also recommended, since persistent WT1 elevation predicts relapse. The team acknowledges the limitations inherent in a single case report, including the unknown status of the fusion gene at the original MDS diagnosis and the absence of autopsy, but the message for clinicians is unambiguous: in this rare leukemia, the enemy is not only the disease itself but the window of time that complications can close before the cure can be delivered.

Subject of Research: A rare case of myelodysplastic syndrome-transformed acute myeloid leukemia with concurrent DEK::CAN fusion gene positivity and WT1 overexpression

Article Title: Myelodysplastic Syndromes‐Transformed Acute Myeloid Leukemia With Concurrent DEK::CAN Fusion Gene Positivity and WT1 Overexpression: A Case Report and Literature Review

Article References: Mao, W., Zhou, T., Xu, X., Luo, S., Jiang, S., & Yu, Z. (2026). Myelodysplastic Syndromes‐Transformed Acute Myeloid Leukemia With Concurrent DEK :: CAN Fusion Gene Positivity and WT1 Overexpression: A Case Report and Literature Review. Cancer Reports, 9(10), Article e70714. https://doi.org/10.1002/cnr2.70714

Image Credits: AI Generated

DOI: 10.1002/cnr2.70714

Keywords: acute myeloid leukemia, myelodysplastic syndromes, DEK::CAN fusion gene, WT1 overexpression, U2AF1 mutation, chromosomal translocation, allogeneic stem cell transplantation, mTOR pathway, alternative splicing, chemotherapy resistance, hematologic malignancy, case report