inv(16)/t(16;16) acute myeloid leukemia with non–type A CBFB-MYH11 fusions associate with distinct clinical and genetic features and lack KIT mutations

Abstract

• Patients with inv(16) non-typeA CBFB-MYH11 fusions lack KIT mutations and have distinct clinical and cytogenetic features.• inv(16) non-type A fusions have a distinct geneexpression profile with upregulation of genes associated with apoptosis, differentiation, and cell cycle.The inv(16)(p13q22)/t(16;16)(p13;q22) in acute myeloid leukemia results in multiple CBFB-MYH11 fusion transcripts, with type A being most frequent. The biologic and prognostic implications of different fusions are unclear. We analyzed CBFB-MYH11 fusion types in 208 inv(16)/t(16;16) patients with de novo disease, and compared clinical and cytogenetic features and the KIT mutation status between type A (n ‫؍‬ 182; 87%) and non-type A (n ‫؍‬ 26; 13%) patients. At diagnosis, non-type A patients had lower white blood counts (P ‫؍‬ .007), and more often trisomies of chromosomes 8 (P ‫؍‬ .01) and 21 (P < .001) and less often trisomy 22 (P ‫؍‬ .02). No patient with non-type A fusion carried a KIT mutation, whereas 27% of type A patients did (P ‫؍‬ .002). Among the latter, KIT mutations conferred adverse prognosis; clinical outcomes of non-type A and type A patients with wild-type KIT were similar. We also derived a fusion-type-associated global gene-expression profile. Gene Ontology analysis of the differentially expressed genes revealed-among others-an enrichment of up-regulated genes involved in activation of caspase activity, cell differentiation and cell cycle control in non-type A patients. We conclude that non-type A fusions associate with distinctclinical and genetic features, including lack of KIT mutations, and a unique gene-expression profile. (Blood. 2013;121(2): 385-391) IntroductionApproximately 5%-7% of acute myeloid leukemia (AML) patients have an inv(16)(p13q22) or t(16;16)(p13;q22) [hereafter referred to as inv(16)/t(16;16)]. [1][2][3] This cytogenetic group is usually associated with high complete remission (CR) rates and a relatively favorable outcome, especially when treated with repetitive cycles of highdose cytarabine as consolidation therapy. 4,5 However, 30%-40% of these patients experience relapse. [6][7][8][9][10] We and others reported that the presence of a KIT mutation confers worse outcome in inv(16)/t(16;16) patients. [10][11][12] Molecularly, inv(16)/t(16;16) results in the juxtaposition of the myosin, heavy chain 11, smooth muscle gene (MYH11) at 16p13 and the core-binding factor, ␤ subunit gene (CBFB) at 16q22, and creation of the CBFB-MYH11 fusion gene. 13,14 Because of the variability of the genomic breakpoints within CBFB and MYH11, more than 10 differently sized CBFB-MYH11 fusion transcript variants have been reported. 15,16 More than 85% of fusions are type A, and 5%-10% each are type D and type E fusions. [15][16][17][18][19][20] Fusion types B, C, and F-K have been reported mostly in single cases. [15][16][17][18][19][20] To our knowledge, only one study examined the biologic and clinical significance of different CBFB-MYH11 fusions, but did not characterize the KIT mutation status. 18 Here, we report the ...

Therapy-related Leukemia with Inv(16)(p13.1q22) and Type D <i>CBFB/MYH11</i> Developing after Exposure to Irinotecan-containing Chemoradiotherapy

“…The cytogenetic and genetic features of AML in the present case were also typical of the type of t-AML caused by topoisomerase II inhibitors, as this type of t-AML characteristically shows balanced recurrent chromosomal translocations, among which inv(16)(p13.1;q22) with CBFB-MYH11 is one of the most frequent (1,12,14). It is also important to note that the non-A fusion types of CBFB-MYH11, such as type D confirmed in the present case, are observed in 40-50% of patients with t-AML, although they are very rare among those with de novo AML with inv(16) (p13.1;q22) (10,11,13), thus suggesting that the AML observed in this case was etiologically, but not simply accidentally, related to the prior chemotherapy regimen. It should also be noted that inv(16)(p13.1q22) is very frequently associated with additional chromosomal translocations, such as trisomies 8, 21 and 22, (10, 11, 19), which were additionally observed in the present patient.…”

“…Molecularly, both inv(16)(p13.1q22) and t(16;16)(p13.1q22) lead to the fusion of the core-binding factor ß-subunit gene (CBFB) at 16q22 with the smooth muscle myosin heavy chain 11 gene (MYH11) at 16p13 (7). Although more than 10 types of CBFB-MYH11 transcripts differing in size have been reported to date, more than 85% of fusions are type A, with the less frequent types D and E reported in 5-10% of patients each (7)(8)(9)(10)(11). Similar to that observed in de novo AML, inv(16)(p13.1q22) is one of the most frequently balanced chromosomal translocations in patients with t-AML.…”

Acute myeloid leukemia with inv(16)(p13.1q22), abnormal eosinophils, and absence of peripheral blood and bone marrow blasts

“…The presence of the PML-RARA fusion transcript was also confirmed by promyelocytic oncogenic domain testing (Fig. 1F) [1] and by quantitative real-time PCR. These results led to the diagnosis of acute promyelocytic leukemia (APL).…”

“…AML with inv(16) accounts for 5-8% of AML and it is usually associated with a relatively favorable prognosis with complete remission rates of 87% [1][2][3]. It usually presents as acute myelomonocytic leukemia and increased eosinophils by morphology in the bone marrow (BM) and/or peripheral blood (PB).…”

“…In a recent study of 208 cases of AML with inv(16)/t(16;16), Schwind et al [1] found that BM blast percentages ranged from 2 to 89%.…”