Rare CBFB-MYH11 fusion transcripts in AML with inv(16)/t(16;16) are associated with therapy-related AML M4eo, atypical cytomorphology, atypical immunophenotype, atypical additional chromosomal rearrangements and low white blood cell count: a study on 162 patients

Abstract

Rare CBFB-MYH11 fusion transcripts in AML with inv(16)/t(16;16) are associated with therapy-related AML M4eo, atypical cytomorphology, atypical immunophenotype, atypical additional chromosomal rearrangements and low white blood cell count: a study on 162 patients The spectrum of CBFB-MYH11 fusion transcripts in acute myeloid leukemia (AML) M4eo with inv(16)/t(16;16) is heterogeneous. Approximately 85% show type A CBFB-MYH11 fusion transcripts. In addition, more than 10 different fusion transcripts have been reported. The prognostic impact and biological background of rare fusion transcripts remain open. In this study, a molecular characterization of CBFB-MYH11 transcripts in 162 patients with CBFB-MYH11 positive AML at diagnosis was performed. In total, 128 patients (79.0%) showed the fusion transcript type A, whereas nine different rare CBFB-MYH11 fusion genes were detected in 34 cases (21.0%). Rare fusion transcripts were found more frequently in therapy-related AML (P ¼ 0.0106). Numerical gains of the chromosomes 8, 21 and 22 were more frequently associated with type A (28.3%) than with rare fusions (12.9%) (P ¼ 0.012). Median white blood cell (WBC) count was higher in type A (35.4 G/l; range ¼ 1.1-279 G/l) than in cases with rare types (7.8 G/l; range ¼ 0.8-148.0 G/l) (Po0.0001). Rare fusion transcripts were correlated with an atypical cytomorphology not primarily suggestive for the FAB subtype M4eo (P ¼ 0.0203). Immunophenotype revealed lower CD2, CD13, CD33 and CD90 levels than in type A fusion cases (P ¼ 0.036, 0.002, 0.029 and 0.045, respectively). However, the type of fusion was not an independent prognostic parameter.

Detection of a novel CBFB/MYH11 variant fusion transcript (K-type) showing partial insertion of exon 6 of CBFB gene using two commercially available multiplex RT-PCR kits

“…As previously reported by Schnittger et al [3], rare fusion transcripts of CBFB/MYH11 are correlated with an atypical cytomorphology and other aberrant characteristics such as AML-M2 morphology or weak monocytic expression (low NSE activity or negativity for CD14). In such a situation, it could be helpful to use multiplex RT-PCR kits to detect rare variant fusion transcripts.…”

“…A total of 10 different CBFB/MYH11 transcripts (A-J subtypes) and other variants have been identified [3e6]. Of all CBFB/MYH11 positive cases, more than 80% have transcript type A, and around 5% each reveals transcripts D and E. Although the type A CBFB/MYH11 transcript shows the typical morphology and other classic characteristics of acute myelomonocytic leukemia with eosinophilia (AML-M4Eo), rare types of fusion transcripts are correlated with an atypical cytomorphology not primarily suggestive for the FrenchAmerican-British (FAB) subtype of AML-M4Eo [3]. In this study, we report on a novel CBFB/MYH11 variant transcript with partial insertion of exon 6 of the CBFB gene using two commercially available reverse transcriptase-polymerase chain reaction (RT-PCR) kits.…”

CBFB–MYH11/RUNX1 together with a compendium of hematopoietic regulators, chromatin modifiers and basal transcription factors occupies self-renewal genes in inv(16) acute myeloid leukemia

“…4 This inversion generates a chimeric gene CBFb-MYH11, which encodes a fusion protein between CBFb and smooth muscle myosin heavy chain (SMMHC/MYH11). [5][6][7][8] Heterozygous Cbfb-Myh11 knock-in mice are embryonic lethal, with definitive hematopoiesis blocked at the stem-cell level. Moreover, adult hematopoietic stem cells fail to differentiate to myeloid and lymphoid lineages, 9 a phenotype similar to that of Runx1 À / À and Cbfb À / À mice 10,11 and suggesting that CBFb-MYH11 is a dominant repressor of RUNX1/CBFb function.…”

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

“…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.…”

“…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. Such cases are most frequently associated with exposure to topoisomerase II inhibitors and commonly involve the non-A types of CBFB-MYH11 (1,10,(12)(13)(14).…”