Rare type I CBFβ/MYH11 fusion transcript in primary acute myeloid leukemia with inv(16)(p13.1q22): a case report

Inv(16)(p13.1q22) in acute myeloid leukemia (AML) is a common chromosomal abnormality. It leads to the core-binding factor ß-subunit (CBFβ)/smooth muscle myosin heavy chain 11 (MYH11) fusion gene. Different breakpoints were observed in the CBFβ gene at 16q22 and the MYH11 gene at 16p13.1. For this reason, different CBFβ/MYH11 fusion genes are generated, with more than 13 types having been reported to date. Type I CBFβ/MYH11 fusion transcripts are very rare, with only 10 cases being reported to date. This case report describes a primary AML patient with inv(16)(p13.1q22) and a rare type I CBFβ/MYH11 fusion gene. The morphological analysis did not conform to the typical M4eo. Abnormal eosinophils were less than 5%, and there was obvious dysgranulopoiesis. The patient was in hematological and genetic remission for 487 days after the initial chemotherapy cycles. However, the CBFβ/MYH11 fusion had been constantly positive. Moreover, the presence of non-type A fusions may affect its biology and clinical prognosis. Therefore, further studies on understanding its biological and prognostic significance are essential.


Case Report
A 50-year-old male farmer complained of fatigue and chest tightness with no obvious cause since March 20, 2019. After resting, his condition improved slightly, but then gradually worsened. The patient visited a local hospital for diagnosis on April 2, 2019. Peripheral blood film (PBF) showed white blood cells (WBC) of 5.6 Â 10 9 /L, red blood cells (RBC) of 1.43 Â 10 12 /L, hemoglobin (Hb) of 53.2 g/L, and platelets (PLT) of 8 Â 10 9 /L. The attending physician recommended a transfer to a tertiary hospital for diagnosis and treatment. The patient was transferred to our hospital on April 4, 2019. Physical examinations showed enlarged bilateral submandibular lymph nodes without hepatosplenomegaly. PBF indicated WBC of 4.20 Â 10 9 /L with 43% neutrophils, 26% lymphocytes, 26% monocytes, and 5% blasts. PBF also revealed RBC of 1.12 Â 10 12 /L with anisocytosis, Hb of 41 g/L, and PLT of 6 Â 10 9 /L. Bone marrow (BM) aspirates revealed a significant increase in bone marrow cellularity; 18% were myeloblasts with regular or irregular nuclei, fine chromatin, visible nucleoli, and reduced blue plasma. Nuclear-cytoplasmic dyssynchrony, nuclear malformations, binuclear, and Pelger malformed granulocytes accounted for 13% of the granulocytes, and 3% abnormal eosinophils were observed. Nucleated red blood cells were significantly reduced and accounted for 1.5%. Petal-nucleated red blood cells and anisocytosis were also observed; 18% of the aspirates were monocytes. Two granular megakaryocytes were observed on the whole slide, and the number of platelets was significantly reduced. Results from the bone marrow biopsy showed hypercellularity of the bone marrow tissue, with an increase in immature cells. Immunophenotyping of bone marrow cells showed 5.65% blasts, expressing CD34, CD117, CD13, HLA-DR, lack of CD7, CD10, CD38, CD33, CD11C, CD11b, CD64, CD15, CD19, CD123, CD56, CD36, CDCR4, CD14, CD300e, CD4, and CD2 (Supplementary Figure S1).
This study was approved by the Ethics Committee of the Traditional Chinese Medical Hospital of Langfang City, China.
CBFb/MYH11 fusion transcripts are heterogeneous and depend on the different intron breakpoints between the exons of CBFb and MYH11 genes. To date, over 13 types of fusions have been reported, the majority of which being type A transcripts, with fewer D and E types, while the other types are rare. Type I fusion transcripts are very rare, with only 10 cases reported in the literature to date. Of the 10 cases, only 6 cases have been reported in detail (1,2,5-7).
We treated a primary AML patient with a rare type I fusion transcript. Morphological analysis did not conform to the typical M4eo. Abnormal eosinophils were less than 5%, and there was obvious dysgranulopoiesis. Chromosome karyotype analysis and FISH assays confirmed the presence of inv(16)(p13.1q22). Gene sequencing showed a type I CBFb/MYH11 fusion transcript. Type I, also known as type S/I, was first reported by Dissing et al. (1), followed by other cases (2)(3)(4)(5)(6)(7). Inv(16)(p13.1q22)/t(16;16)(p13.1; q22) AML with non-type A CBFb/MYH11 fusion transcripts are more common in t-AML patients. Its occurrence has been associated with exposure to topoisomerase II inhibitors/topoisomerase I inhibitors (1,3,6,8). The other fusions that are rarer show a more atypical cytomorphology, mostly with pathologic eosinophils o5% and lower WBC counts (3,4,9). Atypical changes in chromosome numbers have been reported in the literature with chromosomes 8, 21, and 22. Several reports have suggested that the numerical gains in chromosomes 8, 21, and 22 occur mostly in patients with type A rather than rare fusion types (3). However, it has been reported that non-type A patients frequently have extra +8 and +21 chromosomes, with none having extra +22 chromosomes (4). No additional cytogenetic abnormalities and leukopenia were detected at the initial diagnosis in our patient. However, there were obvious abnormalities in granulocyte morphology. Among the reports published in patients with type I, there were 3 cases with t-AML and 5 cases with de novo AML (1,2,4-7).
The patient in this study had de novo AML. This suggests that type I is more common in patients with de novo AML. The type of CBFb/MYH11 fusion transcript is not an independent prognostic factor. No significant differences in overall survival (OS) or event-free survival (EFS) were observed with the type of fusion (3). Previous studies observed no significant differences in CR rate, the cumulative incidence of relapse (CIR), and OS between non-type A patients and type A patients. However, nontype A patients had longer EFS compared to type A patients. This may be related to the presence of KIT mutations rather than the type of fusion transcript. KIT mutations were observed in 24% of type A patients and none in non-type A patients (4). In addition, previous case reports showed that non-type A patients had a high CR rate and a better prognosis (2,5,9,12,13,16). In our patient, next-generation sequencing showed no genetic mutations related to prognosis. After a limited number of chemotherapy cycles, the patient was in hematological and genetic remission 487 days after the initial chemotherapy. However, the CBFb/MYH11 fusion had been always positive.
The patient is currently undergoing regular chemotherapy and follow-up.
The limitation of this study is that the interphase FISH specimens could not be saved due to a long experimental time, and metaphase FISH could not be performed.
It is currently believed that the type of fusion has no effect on the prognosis of patients with inv(16)(p13.1q22)/t (16;16)(p13.1;q22). However, the presence of non-type A fusions, related distinctive clinical and genetic characteristics, and unique gene expression profiles may affect its biology and clinical outcome. Due to the limited number of CBFb/ MYH11 fusion types, understanding its biological and prognostic significance is challenging.