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.
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.
Roche-Lestienne
Catherine
C
Cancer Research Institute of Lille, JP Aubert Center, Inserm Unit 837, France. c-roche-lestienne@chru-lille.fr
Deluche
Lauréline
L
Corm
Sélim
S
Tigaud
Isabelle
I
Joha
Sami
S
Philippe
Nathalie
N
Geffroy
Sandrine
S
Laï
Jean-Luc
JL
Nicolini
Franck-Emmanuel
FE
Preudhomme
Claude
C
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*
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