In:
Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 2786-2786
Abstract:
Background: Besides the extensively studied point mutations in the BCR/ABL TK domain as the clinically most important cause of imatinib (IM) resistance either in CML and Philadelphia-positive (Ph+) ALL, additional acquired genetic events contributing to resistance/disease progression are not fully understood. Many evidences suggest that the enhanced survival and differentiation arrest of the CML blast crisis (BC) cells depends on the cooperation of BCR/ABL with other genes deregulated during disease progression. A recent study has identified RUNX1/AML1 transcription factor gene as a modulator of the cellular response towards IM in vitro and in vivo in mice, suggesting its possible involvement in disease persistence in IM-resistant CML patients. Purpose: We investigated RUNX1 molecular abnormalities (point mutations or cryptic chromosomal RUNX1 translocation to a novel recently described gene partner PRDM16 at 1p36) in 18 Ph+ leukemias. The observation that RUNX1 mutated allele is frequently duplicated by acquired trisomy of the altered chromosome 21 in acute myeloblastic leukemias (AML) prompt us to focus our analysis on a selected cohort (1 CP-CML, 3 AP-CML, 8 myeloid BC, 1 lymphoid BC, 2 de novo Ph+ ALL-B, 1 de novo AML and 1 therapy-related- Ph+ ALL) presenting acquired trisomy 21 along disease course. Methods: From peripheral blood leucocytes, recurrent mutations were investigated by sequencing DNA PCR fragments corresponding to exon 3 to 8 of RUNX1. RUNX1-PRDM16 fusion was investigated by RT-PCR (i.e. RUNX1 exon 5-PRDM16 exon 2 junction) and by FISH using the TEL/AML1 dual color/dual fusion translocation probes (Vysis, Downer’s grove, IL, USA). Results: We report a high frequency (33%) of recurrent point mutations (4 in myeloid BC CML and 1 in CP-CML) within the DNA-binding region of RUNX1. We did not find any mutation in de novo BCR/ABL+ ALLs or lymphoid BC CMLs. Onset of RUNX1 mutations was detected at diagnosis or before the acquisition of trisomy 21. We also report a high frequency of RUNX1-PRDM16 fusion for 3 out of 7 investigated patients: 2 CMLs and, for the first time reported to our knowledge, 1 therapy-related BCR/ABL+ ALL. RUNX1-PRDM16 is probably transcribed at low levels since only few bone marrow metaphases with trisomy 21 were t(1;21)(p36;q22) positive. Two patients presented both RUNX1 mutations and RUNX1-PRDM16 fusion. All these events are associated with a poor survival: 14 out of 18 patients died with a median survival of 3 months after the diagnosis of the acquired clonal trisomy 21. Furthermore, none of the patients in our study raised durable optimal responses to IM. Conclusion: Our data 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. Our findings also support that it may exist a heterogeneous genetic status at diagnosis of CML, underlying the need of further investigations able to define more precisely the molecular disease characteristics at diagnosis for better therapeutic decision adjustments.
Type of Medium:
Online Resource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood.V110.11.2786.2786
Language:
English
Publisher:
American Society of Hematology
Publication Date:
2007
detail.hit.zdb_id:
1468538-3
detail.hit.zdb_id:
80069-7
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