title: RUNX1 DNA-binding mutations and RUNX1-PRDM16 cryptic fusions in BCR-ABL+ leukemias are frequently associated with secondary trisomy 21 and may contribute to clonal evolution and imatinib resistance.
abstract: Acquired molecular abnormalities (mutations or chromosomal translocations) of the RUNX1 transcription factor gene are frequent in acute myeloblastic leukemias (AMLs) and in therapy-related myelodysplastic syndromes, but rarely in acute lymphoblastic leukemias (ALLs) and chronic myelogenous leukemias (CMLs). Among 18 BCR-ABL+ leukemias presenting acquired trisomy of chromosome 21, we report a high frequency (33%) of recurrent point mutations (4 in myeloid blast crisis [BC] CML and one in chronic phase CML) within the DNA-binding region of RUNX1. We did not found any mutation in de novo BCR-ABL+ ALLs or lymphoid BC CML. Emergence of the RUNX1 mutations was detected at diagnosis or before the acquisition of trisomy 21 during disease progression. In addition, we also report a high frequency of cryptic chromosomal RUNX1 translocation to a novel recently described gene partner, PRDM16 on chromosome 1p36, for 3 (21.4%) of 14 investigated patients: 2 myeloid BC CMLs and, for the first time, 1 therapy-related BCR-ABL+ ALL. Two patients presented both RUNX1 mutations and RUNX1-PRDM16 fusion. These events are associated with a short survival and support the concept of a cooperative effect of BCR-ABL with molecular RUNX1 abnormalities on the differentiation arrest phenotype observed during progression of CML and in BCR-ABL+ ALL.
authors.affiliation: Cancer Research Institute of Lille, JP Aubert Center, Inserm Unit 837, France. c-roche-lestienne@chru-lille.fr
authors.forename: Catherine
authors.initials: C
authors.lastname: Roche-Lestienne
authors.forename: Lauréline
authors.initials: L
authors.lastname: Deluche
authors.forename: Sélim
authors.initials: S
authors.lastname: Corm
authors.forename: Isabelle
authors.initials: I
authors.lastname: Tigaud
authors.forename: Sami
authors.initials: S
authors.lastname: Joha
authors.forename: Nathalie
authors.initials: N
authors.lastname: Philippe
authors.forename: Sandrine
authors.initials: S
authors.lastname: Geffroy
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Laï
authors.forename: Franck-Emmanuel
authors.initials: FE
authors.lastname: Nicolini
authors.forename: Claude
authors.initials: C
authors.lastname: Preudhomme
mesh_terms: D000208:Acute Disease; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001549:Benzamides; D001752:Blast Crisis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D002877:Chromosomes, Human; D002908:Chronic Disease; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D007938:Leukemia / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D010641:Phenotype; D010879:Piperazines / Q000008:administration & dosage* / Q000009:adverse effects; D017354:Point Mutation; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects; D012189:Retrospective Studies; D015996:Survival Rate; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014178:Translocation, Genetic / Q000187:drug effects / Q000235:genetics; D014314:Trisomy / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; C416371:PRDM16 protein, human; D010879:Piperazines; D011743:Pyrimidines; C493728:RUNX1 protein, human; D014157:Transcription Factors; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl