Novel RUNX1‐PRDM16 fusion transcripts in a patient with acute myeloid leukemia showing t(1;21)(p36;q22)

Abstract

The t(1;21)(p36;q22) is a recurrent chromosome abnormality associated with therapy-related acute myeloid leukemia (AML). Although involvement of RUNX1 has been detected by fluorescence in situ hybridization analysis, the partner gene has not been reported previously. We identified a novel RUNX1 partner gene, MDS1/EVI1-like-gene 1 (PRDM16), in an AML patient with t(1;21). Alternative splicing of the fusion gene generates five different fusion transcripts. In two of them, the PRDM16 reading frame is maintained in the fusion with RUNX1, suggesting that the RUNX1-PRDM16 gene fusion results in the production of a protein that is highly homologous to the RUNX1-MDS1/EVI1 chimeric protein. It is suggested that PRDM16 and MDS1/EVI1 share a common molecular mechanism for the leukemogenesis of RUNX1-associated leukemia. Characterization of the RUNX1-PRDM16 fusion protein and comparison with the RUNX1-MDS1/EVI1 protein will facilitate the understanding of the mechanisms underlying RUNX1-associated leukemia.

Overexpression of sPRDM16 coupled with loss of p53 induces myeloid leukemias in mice

“…In both cases, expression of PRDM16 is altered, either as a consequence of its juxtaposition to the enhancer element of RPN1 at 3q21 (10,11) or to its fusion with AML1 (AML1/PRDM16) at 21q15 (12)(13)(14). AMLs carrying t(1;3)(p36;q21) translocations present with a characteristic disease phenotype of trilineage dysplasia, dysmegakaryocytopoiesis, normal to elevated platelet counts, poor response to chemotherapy, and poor prognosis (15).…”

Downregulation of Prdm16 Is Critical for HOXB4-mediated Benign HSC Expansion In Vivo

“…Expression of PRDM3 and PRDM16 that lack partial PR domain leads to myeloid leukemia and adult T-cell leukemia due to chromosome translocation events or viral vector insertional activation. [219][220][221][222][223][224][225][226][227] Prdm1 and Prdm14 are essential for pluripotent primordial germ cells (PGCs) generation and Prdm1 mutants and Prdm14 mutants were not able to generate PGCs. [228][229][230][231] Prdm14 is also required to maintain mouse ESCs at pluripotent state even though Prdm14 is not required for mouse ESC derivation.…”

“…238 Aberrant expression of MEL1S gene due to chromosome translocation and vector insertional activation was associated with MDS/AML and T-cell leukemia. [223][224][225][226][238][239][240] Prdm16 is mouse homolog of human PRDM16/MEL1 and its protein structure is shown in Figure 1-5.…”

“…Since PRDM16/MEL1 was first isolated from t(1;3)(p36;q21)-positive MDS/AML patient leukemia cells, 237 there are growing evidences showing sPRDM16/MEL1S, lacking most of PR domain, is the major isoform highly expressed in t(1;3)(p36;q21)-positive MDS/AML as fusion partner with RPN1 238,239 and t(1;21)(p36;q22)-positive therapyrelated MDS/AML as fusion partner of RUNX1. 224,225,247 The RUNX1-PRDM16 gene is highly homologous to MDS1/EVI1 gene, 237 suggesting RUNX1-PRDM16 may share similar mechanism in leukemic progress. sPRDM16 is also overexpressed in adult T cell leukemia with normal karyotype leukemias due to hypomethylation of regions surrounding sPRDM16 transcription start site 223 .…”

“…PRDM16 as mentioned before is required for HSC maintenance duringembryogenesis 215,216 and its aberrant expression is frequently detected in MDS/AML or T-ALL patients. [223][224][225][237][238][239]247,259,260 Downregulation of Prdm16 by HOXB4 can serve a mechanism to prevent leukemia in transplanted mice. Due to chromosome translocation or vector insertional activation, short form of PRDM16 (sPRDM16) lacking most of the PR domain is the major isoform expressed in leukemia patients.…”