t(3;8)(q26.2;q24) Often Leads to MECOM/MYC Rearrangement and Is Commonly Associated with Therapy-Related Myeloid Neoplasms and/or Disease Progression

Abstract

t(3;8)(q26.2;q24) is a rare recurrent cytogenetic abnormality that is associated with myeloid neoplasms. Of 20 patients with t(3;8)(q26.2,q24), 8 had therapy-related acute myeloid leukemia (AML), 3 therapy-related myelodysplastic syndrome, 4 blast phase of chronic myeloid leukemia, 1 relapsed AML, 1 AML transformed from chronic myelomonocytic leukemia, 1 blast phase of an unclassifiable myeloproliferative neoplasm, 1 de novo myelodysplastic syndrome, and 1 de novo AML. Nineteen patients presented with cytopenia. Multilineage dysplasia was observed in 16/18 patients, and megakaryocytes were markedly decreased in 11/20 patients. Blasts showed a primitive myeloid immunophenotype in 17 patients, negative for myeloperoxidasein in 14/17, and aberrant CD7 expression in 5/17 patients. Fluorescence in situ hybridization showed MECOM rearrangement in 18/19 and MYC in 16/18 patients. Myc was shown to be expressed in all 14 cases assessed. Gene mutation testing was performed in 14 patients, and 7 showed at least one mutation including ASXL1 (2/6), TET2 (2/6), SRSF2 (2/6), and NRAS (2/13). At last clinical follow-up, 18 patients died and 2 were alive with persistent disease, with a median survival of 6 months. The authors conclude that t(3;8)(q26.2;q24) often leads to MECOM and MYC rearrangement, occurs predominantly in therapy-related myeloid neoplasms or at disease progression, and shares some similarities with myeloid neoplasms associated with inv(3)/GATA2-MECOM. Patients with myeloid neoplasms associated with t(3;8)(q26.2;q24) have a dismal outcome.Had occupational exposure to methylenechloride and 1, 1, 1-trichloroethane.

MYC: a multipurpose oncogene with prognostic and therapeutic implications in blood malignancies

“…Unlike lymphoid malignancies, where MYC overexpression is mostly associated with its translocation, the cause of MYC aberrant expression and activity in myeloid malignancies is not thoroughly established [ 29 , 608 ]. However, a rare recurrent translocation t(3;8) (q26.2;q24), causing MECOM-MYC rearrangement, has been reported to be associated with therapy-related and relapsed AML as well as AML transformed from Ph + CML [ 609 , 610 ]. Recently, in a detailed and comprehensive study, hotspot mutations in the MYC gene have been identified in AML patients [ 611 ].…”

The leukemic oncogene EVI1 hijacks a MYC super-enhancer by CTCF-facilitated loops

“…AML is a heterogeneous disease, with EVI1 positive (EVI1+) inv(3)/t(3;3) patients being identified as a subgroup with a very poor response to therapy [16][17][18][19] . Besides inv(3)/t(3;3), many other EVI1 + AML cases with 3q26 rearrangements have been reported, including translocations t(2;3)(p21;q26), t(3;7)(q26;q24), t(3;6)(q26;q11), and t(3;8)(q26;q24) 18,[20][21][22][23][24][25][26][27] . We hypothesize that in all these rearrangements EVI1 overexpression is induced by the repositioning of an enhancer that can interact with the EVI1 promoter, as shown for inv(3)/t(3;3) AML 14,15 .…”

“…We hypothesize that in all these rearrangements EVI1 overexpression is induced by the repositioning of an enhancer that can interact with the EVI1 promoter, as shown for inv(3)/t(3;3) AML 14,15 . We performed targeted next-generation sequencing (NGS) of the long arm of chromosome 3 (3q-seq) in translocation t(3;8)(q26;q24) AML harboring an EVI1/MYC rearrangement 22,27 . Applying CRISPR-Cas9 technology, we generated a human t(3;8) cell line model with an eGFP reporter cloned 3' of EVI1.…”

Data on MECOM rearrangement-driven chromosomal aberrations in myeloid malignancies

“…Conventional G-banded chromosomal analysis (karyotyping) has been routinely performed on unstimulated 24-h and 48-h BM aspirate cultures using standard techniques as we have reported previously [6] , [7] , [8] . Interphase-, metaphase-, map-back FISH and WCP have been performed by following existing laboratory protocols as reported previously [6] , [7] , [8] , [9] . The following probe/probe set have been employed for this study.…”