Cytogenetic changes are diagnostically and prognostically significant in the case of acute myeloid leukaemia (AML). However, for certain rare cytogenetic changes, including t(11; 12) (p15; q13), t(16; 21) (p11; q22) (1) and t(8; 17; 15; 21) (q22; q15; q23; q22) (2), the pathogenesis, clinical features and impact of the cytogenetic changes on the biological characteristics of the leukaemic cells of these patients remain unclear due to the low incidence of these changes. In the present study, we report the case of a leukaemia patient, recently diagnosed at the Zhongshan Hospital of Xiamen University, China, whose morphological and immunological manifestations were consistent with acute monocytic leukaemia (AML-M5b), and who demonstrated a rare chromosomal change of t(11; 12) (p15; q13) along with a positive FLT3-ITD mutation. The clinical features and therapeutic responses are presented in the case report. Written informed consent was obtained from the patient and ethical approval was obtained from the Medical Ethics Committee of Zhongshan Hospital of Xiamen University (Xiamen, China).

In 1998, Wong et al (3) reported the first case of AML that developed following radiotherapy for breast cancer, demonstrating a karyotype of t(11; 12) (p15; q13), following administration of a dose-adjusted daunorubicin and Ara-c (cytarabin) (DA) regimen chemotherapy. Complete remission (CR) was achieved and re-examination revealed that the chromosomes exhibited a normal karyotype. In 2002, Taketani (4) et al reported a case of primary AML-M1 with t(11; 12) (p15; q13). CR was observed one month after the administration of the ANLL-91 regimen. This patient received haematopoietic stem cell transplantation 9 months later and succumbed due to a relapse after six months of sustained remission. Taketani et al identified an NUP98-HOXC11 gene fusion caused by the t(11; 12) translocation for the first time. In 2003, La Starza et al (5) also reported a case of primary AML-M2 with t(11; 12) (p15; q13) chromosome translocation, and confirmed the formation of the NUP98-HOXC13 fusion gene (6). Subsequently, a number of cases of such chromosomal abnormalities in leukaemia were reported, including AML-M2a, M2, M4 and M5b (6–8). To date, four cases of positive NUP98-HOXC13 and NUP98-HOXC11 fusion genes have been reported (3,6–8). In 2009, La Starza et al (9) again identified a case of AML-M2 with t(11; 12) (p15; q13). However, the fluorescence in situ hybridisation method failed to detect the NUP98-HOXC13 and NUP98-HOXC11 fusion genes.

In 2011, Such et al (10) published a study on a 35-year-old male diagnosed with acute promyelocytic leukaemia (APL) in accordance with the French-American-British (FAB) criteria, but lacking the PML-RARα fusion gene. The patient's karyotype was also t(11; 12) (p15; q13), which formed the NUP98-RARr fusion gene. In this fusion gene, the NUP98 breakpoint was located on exon 12, and the RARr breakpoint was located on exon 4. There was a complete absence of HOXC11, HOXC13 and PML-RARα fusion genes. This patient had a WBC count of 12×10⁹/l and achieved CR after receiving the standard DA chemotherapy without tretinoin treatment. Later on, the patient underwent autologous stem cell transplantation and remained in CR at the 8-month follow-up point. In 2013, Gong et al (11) also reported two cases of APL with karyotype t(11; 12) (p15; q13). Neither of the patients underwent tests to detect HOXC11 and HOXC13 fusion genes, and the tretinoin and arsenic trioxide therapies were ineffective. One of the patients had a WBC count of 14.6×10⁹/l at the time of diagnosis. No remission was achieved following the DA chemotherapy and subsequent myeloablative chemotherapy, and the patient succumbed to infection. The patient had a WBC count of 3.7×10⁹/l and positive FLT3-TKD; CR was achieved following high-dose asparaginase (HDA) chemotherapy. Subsequently, the patient remained in CR following two courses of consolidation chemotherapy.

A study by Gu et al (7) revealed that the NUP98 gene on chromosome 11p15 encodes the protein associated with a nuclear pore complex, which regulates the nucleocytoplasmic transport of proteins and mRNA. Mouse bone marrow transplantation experiments revealed that the NUP98 fusion protein causes leukaemia, and that the translocation of the NUP98-HOXA9 fusion protein of the bone marrow cells causes AML in mice. The NUP98-HOXC11 fusion protein is not involved in HOXC11 transcriptional regulation, but promotes the expression of the upstream reporter gene as a reverse activator. In addition, t(11; 12) (p15; q13) unbalanced translocation may lead to a loss of significant tumour suppressor genes on the telomere of chromosome 11p, which may also be one of the key mechanisms that lead to leukaemia.

AML patients with t(11; 12) (p15; q13) undergo primary or secondary clonal changes, which may return to normal following treatment. La Starza et al (5) reported a new t(1; 21) (p32; q22) karyotype that occurred in a patient with relapsed AML. Masuya et al (12) published a study on a 55-year-old female patient with therapy-related myelodysplastic syndrome who had normal karyotype chromosomes at diagnosis, but demonstrated t(1; 2) (p36; p21) and secondary t(11; 12) (p15; q13) when the relapse occurred. This patient survived for more than 6 years. In the cases of secondary AML reported by Wong et al (3) and APL reported by Gong et al (11), the chromosomes returned to the normal state following DA chemotherapy.

Thus, the t(11; 12) (p15; q13) chromosomal abnormality is a rare recurrent genetic event in AML, and may occur in primary AML or in chemotherapy-related secondary AML. Various subtypes of AML with t(11; 12) (p15; q13) have been reported, with the exception of M6 and M7. To date, 13 AML patients with t(11; 12) (p15; q13) between the ages of 2 and 59 years have been reported. Males account for 40% and females for 60% of patients. Among these patients, the WBC count was generally in the range 3.5–25×10⁹/l, with the exception of one patient, in whom it reached 211×10⁹/l. Taken together, the t(11; 12) (p15; q13) chromosomal abnormality exhibits strong heterogeneity, and the translocation may involve different genes or may have different breakpoints even when the same genes are involved. However, the pathogenic mechanism and the prognosis remain unclear.

AML with t(11; 12) (p15; q13) combined with FLT3-ITD mutations has also been reported (8,13). These patients succumbed in the early stages following treatment, indicating poor prognosis (13). However, the prognosis of the FLT3-TKD mutation is relatively superior. In the APL patient with FLT3-TKD mutations reported by Gong et al (11), CR was achieved following one course of HDA remission induction. This patient's chromosomes returned to normal and the FLT3-TKD was observed to be negative. The patient remained in CR following two subsequent courses of consolidation treatment.

In the patient reported in the present study, one of the molecular biological characteristics of leukaemia was the combination of the FLT3-ITD mutation and a negative NPM1 gene. The FLT3-ITD mutation-positive AML cases often have a poor outcome, and demonstrate a poor response to chemotherapy, leading to a low remission rate and high early mortality (14–16). The positive expression rate of the NPM1 gene is 20–50% in newly diagnosed AML patients, and AML patients expressing the NPM1 gene have a relatively superior prognosis (17). The clinical efficacy (including CR, event-free survival and overall survival rate) of the AML patients with FLT3-ITD mutations and positive NPM1 gene expression is superior to that of patients with only positive FLT3-ITD mutations (18–20). Most of the literature suggests that clinical features of FLT3-ITD mutation-positive patients include a high number of peripheral blood leukocytes and a high percentage of leukaemia cells in the bone marrow (16,21). At the time of diagnosis, the WBC count of our patient was 76.41×10⁹/l, and the monoblasts and premonocytes accounted for 75% of bone marrow cells. This result was consistent with the previous reports in literature. However, this patient did not exhibit any symptoms of leukaemia infiltration. Unlike the patients with FLT3-ITD mutations who succumbed during the early stages, this patient responded positively to the IA chemotherapy, which quickly eliminated the leukaemia cell clones. However, the proliferation rate of the leukaemia cells was high during the intermission of chemotherapy. Four weeks after chemotherapy, the proportion of immature bone marrow cells was 38%, which remained unchanged after another course of IA chemotherapy. Subsequently, two courses of chemotherapy could still not achieve a complete haematological remission, as indicated by the fact that the proportion of bone marrow immature cells remaining were only 40% of the expected total. It was speculated that the patient's rapid proliferation of leukaemia cells may be related to the FLT3-ITD gene mutation. Under normal circumstances, the juxtamembrane region and the ‘activation loop’ of tyrosine kinase receptors exhibit a self-inhibiting function to maintain an inactive conformation of the kinase. An FLT3-ITD mutation leads to the continuous activation of the tyrosine kinases, thus causing a spontaneous and non-dependent excessive proliferation of cells.

Currently, studies on the immunology and cytogenetic features of FLT3-ITD mutation-positive AML are scarce (22,23). Among the 14 cases of AML with t(11; 12) (p15; q13) reported, including the present case, 21% (3 cases) demonstrated an FLT3-ITD mutation. Further cases need to be studied to determine whether a correlation exists between the FLT3-ITD mutation and t(11; 12) (p15; q13).

In conclusion, AML patients with t(11; 12) (p15; q13) combined with FLT3-ITD mutations are expected to have a short life expectancy; however, an early haematopoietic stem cell transplantation therapy may improve the treatment outcome for these patients (10,24).