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Blood, 1 April 2008, Vol. 111, No. 7, pp. 3735-3741.
Prepublished online as a Blood First Edition Paper on January 17, 2008; DOI 10.1182/blood-2007-07-102533.
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Submitted July 24, 2007
Accepted January 5, 2008
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
Catherine Roche-Lestienne*, Laureline Deluche, Selim Corm, Isabelle Tigaud, Sami Joha, Nathalie Philippe, Sandrine Geffroy, Jean-Luc Lai, Franck-Emmanuel Nicolini, and Claude Preudhomme
Cancer Research Institute of Lille, JP Aubert Center, Inserm Unit 837 and Northwest Canceropole, Lille, France
Hematology Department, Hurriez Hospital - CHRU, Lille, France
Laboratory for Hematology and Cytogenetics, CHLS, Pierre Benite, France
Laboratory for Hematology, Biology and Pathology Center - CHRU, Lille, France
Laboratory for Medical Genetics, CHRU, Lille, France
Hematology Department, E. Herriot Hospital, Lyon, France
* Corresponding author; email: c-roche-lestienne{at}chru-lille.fr.
Acquired molecular abnormalities (mutations or chromosomal translocations) of the RUNX1 transcription factor gene are frequent in acute myeloblastic leukemias (AML) and in therapy-related myelodysplastic syndromes, but rarely in acute lymphoblastic leukemias (ALL) and chronic myelogenous leukemias (CML). 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 out of 14 investigated patients (21.4%): 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.
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