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ctt-journal > Aleinikova et al. (Abstract)

Aleinikova et al. (Abstract)

Cellular Therapy and Transplantation (CTT), Vol. 3, No. 12
doi: 10.3205/ctt-2011-No12-abstract61

© The Authors. This abstract is provided under the following license: Creative Commons Attribution 3.0 Unported

Abstract accepted for "5th Raisa Gorbacheva Memorial Meeting Hematopoietic Stem Cell Transplantation in Children and Adults", Saint Petersburg, Russia, September 18–20, 2011

Preliminary Program

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The significance of MLL-rearrangements in pediatric patients with leukemia

Olga V. Aleinikova, Anatoly M. Kustanovich

Belarusian Research Center for Pediatric Oncology and Hematology, Minsk, Belarus

Correspondence: Olga V. Aleinikova, Belarusian Research Center for Pediatric Oncology and Hematology, PO Lesnoe-2, Minsk, 223040, Belarus, E-mail: aleinikova2004@spam is badmail.ru

Abstract

MLL-rearrangements are widespread aberrations in hemoblastoses. They are detected in 5–10% of ALL in adults and children, in AML, MDS, and biphenotypic leukemia. Eighty percent of infant leukemia and 25% of secondary/therapy-related leukemias are characterized by MLL-rearrangements. Aberrations of the MLL gene are involved in pathogenesis of some types of leukemia and their detection can be associated with poor outcomes.

The aim of the work was to analyze the molecular-biological features of MLL-rearrangements and their application for prognosis and MRD monitoring.

Methods: Aberrations of the MLL-gene (principally MLL-AF4, MLL-AF6, MLL-AF9, MLL-Af10, MLL-ENL, and MLL-ELL) were detected in bone marrow blast cells of de novo pediatric patients with acute leukemia using multiplex PCR and molecular cytogenetics. MRD analysis was performed using real time PCR. Mutations of NPM1, WT1, and CEBPA were detected using fragment analysis and/or sequencing.

Results: Some degree of linear specificity was detected for MLL-rearrangements. MLL-AF4 and MLL-ENL were expressed predominantly in ALL (in 6.1% and 2.3% of B-linage ALL), while MLL-AF9 and MLL-AF10 were found mainly in AML (in 9.5% and 5.3%), while this specificity was relative. Survival analysis showed that patients with MLL-rearrangements had significantly worse outcomes in comparison with patients without rearrangements (17% vs. 41% for EFS, 25% vs. 51% for RFS). Survival of children with MLL-AF9 was comparable with that of patients without expression of the gene, while patients with MLL-AF10 had a worse prognosis when compared with the control group. Poor prognosis was typical for ALL with MLL-AF4.

Analysis of cooperative mutations revealed that all patients with MLL-rearrangements had NPM1wt (n=21), in 1 patient (6%) CEBPAmut was detected, in 2/22 (9%) a mutation of WT1 and in 1/22 (4.5%) FLT3-ITD was detected.

Heterogeneity of fusion partners of the MLL gene and a variety of transcript variants requires a careful approach when monitoring MRD. MRD monitoring was available for ALL and AML patients with expression MLL-AF4, MLL-AF9, MLL-ENL, and MLL-ELL in blast cells. It was shown that the level of chimeric MLL transcript may correspond with the response of the leukemic clone to treatment and predict a development of relapse.

Conclusion: Acute leukemia with MLL-rearrangements is generally associated with unfavorable prognosis, although the outcome may depend upon the type of fusion gene. Analysis of aberrations of MLL gene is of clinical value for risk group stratification and for minimal residual disease monitoring.

Keywords: acute leukemia, childhood, MLL-rearrangements, prognosis, MRD