PRDM16 (1p36) translocations define a distinct entity of myeloid malignancies with poor prognosis but may also occur in lymphoid malignancies

Abstract

SummaryThe PRDM16 (1p36) gene is rearranged in acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) with t(1;3)(p36;q21), sharing characteristics with AML and MDS with MECOM (3q26.2) translocations. We used fluorescence in situ hybridization to study 39 haematological malignancies with translocations involving PRDM16 to assess the precise breakpoint on 1p36 and the identity of the partner locus. Reversetranscription polymerase chain reaction (PCR) was performed in selected cases in order to confirm the partner locus. PRDM16 expression studies were performed on bone marrow samples of patients, normal controls and CD34 + cells using TaqMan real-time quantitative PCR. PRDM16 was rearranged with the RPN1 (3q21) locus in 30 cases and with other loci in nine cases. The diagnosis was AML or MDS in most cases, except for two cases of lymphoid proliferation. We identified novel translocation partners of PRDM16, including the transcription factors ETV6 and IKZF1. Translocations involving PRDM16 lead to its overexpression irrespective of the consequence of the rearrangement (fusion gene or promoter swap). Survival data suggest that patients with AML/MDS and PRDM16 translocations have a poor prognosis despite a simple karyotype and a median age of 65 years. There seems to be an over-representation of lateonset therapy-related myeloid malignancies.

Recurrent PRDM10 Gene Fusions in Undifferentiated Pleomorphic Sarcoma

“…Several other members of the PRDM family are associated with cancer and gene fusions involving PRDM16 have been reported in cases of acute myelogenous leukemia and myelodysplastic syndrome. PRDM16 can have several partner genes and all reported fusions lead to overexpression of parts of the gene, usually not containing the PR domain, or the complete gene by promoter swapping (20).…”

t(1;3)(p36;q21) RPN1/PRDM16

“…Myelodysplastic syndromes and acute myeloid leukaemias Note A t(1;3)(p36;q21) RPN1/PRDM16 was found in 35 cases (Mochizuki et al, 2000;Shimizu et al, 2000: Xinh et al, 2003Duhoux et al, 2012) Phenotype/cell stem origin There were 19 myeloproliferative/myelodysplastic syndromes: 1 chronic myeloid leukemia (CML), 3 refractory anaemia with ring sideroblasts (RARS); 6 refractory anemia with excess blasts (RAEB, RAEB2, RAEB-T), 6 chronic myelomonocytic leukaemia (CMML) and 3 myelodysplastic syndrome not otherwise specified (MDS-NOS); and 16, acute myeloid leukaemias; 7 apparently de novo (AML-M1, M2, M4, M5a, M6 and NOS), and 9 therapy-related or secondary AML.…”

“…It could serve as an enhancer, to activate transcription of PRDM16 (Mochizuki et al, 2000;Shimizu et al, 2000). Overexpression of PRDM16 (Duhoux et al, 2012).…”

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

“…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.…”

“…We focused on the study of sPrdm16 because of the association of sPrdm16 with human MDS/AML and T-TALL. 239,247,260 Humphries group also reported the vector insertional activation of sPrdm16 which plays role in the myeloid leukemia developed in large animals transplanted with HOXB4 transduced CD34 + cells. 187 At meanwhile Forget's group screened 52 HOXB4 transplanted mice and 2 mice developed AML at 4 and 9.5 months, respectively, following transplantation.…”