Abstract
Chromosome translocation t(12;22)(p13;q12)/MN1-ETV6 and MN1 overexpression confer a subset of adverse prognostic AML but so far lack in-depth research. We focused on the clinical course and comprehensive genetic analysis of eight cases with t(12;22)(p13;q12) and one with t(12;17;22) (p13;q21;q13) to elucidate their molecular etiology and outcomes of allogeneic hemopoietic stem cell transplantation (allo-HSCT). The total incidence of t(12;22)(p13;q12) and related translocations was 0.32% in myeloid neoplasms. These patients were confirmed to have dismal prognosis when treated only with chemotherapy, and we firstly provided evidence that they can significantly benefit from timely allo-HSCT. Five cases were MN1-ETV6 positive, and a novel MN1-STAT3 fusion was identified in the patient with triadic translocation. Significant MN1 overexpression was observed in all three MN1-fusion-negative cases. Genetic analysis highlighted the evidence of an ectopic super-enhancer associated orchestrated mechanism of MN1 overexpression and ETV6 haploinsufficiency in t(12;22)(p13;q12) myeloid neoplasms, rather than the conventional thought of MN1-ETV6 fusion formation. We also disclosed the high concomitance of trisomy 8 and 531 Kbps focal 8q duplication in t(12;22)(p13;q12) cases. The new perspective about this entity of disease will enlighten further research to define the mechanism of tumorigenesis and discover effective treatments for MN1-driven malignancies.
Highlights
Translocation of t(12;22)(p13;q12) is a rare but recurrent chromosomal abnormality in hematologic malignancies involving meningioma 1 (MN1) and ETS variant 6 (ETV6) genes [1]
The cases included three acute myeloid leukemia (AML)-M5, one AML-M2, one AML progressed from myelodysplastic syndrome (MDS) (MDS-AML), one MDS with excess blasts 2 (MDS-EB-2), one chronic myelomonocytic leukemia (CMML), and two myeloid/T mixed-phenotype acute leukemia (MPAL) (Table 1)
Standard 30 × Whole-genome sequencing (WGS) was performed on diagnostic bone marrow (BM) samples from cases that were negative for MN1-ETV6
Summary
Translocation of t(12;22)(p13;q12) is a rare but recurrent chromosomal abnormality in hematologic malignancies involving meningioma 1 (MN1) and ETS variant 6 (ETV6) genes [1]. More than 40 cases with t(12;22)(p13; q12) have been reported so far, MN1-ETV6 and the reciprocal ETV6-MN1 fusion transcripts were confirmed in only a dozen of them [1]. The translocation has been reported only in myeloid neoplasms, most of which are acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with poor responses to chemotherapy [1]. The pathogenic mechanism of t(12;22)(p13;q12) and the fact that a considerable proportion of cases with this translocation lack fusion transcripts remain mysterious. Whether the central pathogenesis lies in the fusion of MN1ETV6 or ETV6-MN1 remains elusive [4]. We focused here on AML cases with t(12;22)(p13;q12) to elucidate their molecular etiology and outcomes of allogeneic hemopoietic stem cell transplantation (allo-HSCT) treatment
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