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Deletion of the multidrug resistance-associated protein (MRP1) gene in acute myeloid leukemia with inversion of chromosome 16 has no prognostic impact

Leukemia volume 14, page 1154 (2000)Cite this article

Acute myelomonocytic leukemia with bone marrow eosinophilia (AML FAB M4Eo) is a distinct subtype of acute myeloid leukemia (AML) which is associated with the chromosomal inversion inv(16)(p13q22) resulting in fusion of the MYH11 gene on 16p13 with the CBFβ gene on 16q22.1 In prospective studies it has been shown that AMLs with inv(16) are associated with a high complete remission (CR) rate and long remission durations when treated with high-dose cytarabine in postremission therapy.2 Recently, deletions of sequences 150 to 350 kb in size centromeric to the p-arm breakpoint were described in subsets of 14% to 38% of AMLs with inv(16).3456 The affected genomic region contains two members of the superfamily of transmembrane transporters, the multidrug resistance-associated protein gene (MRP1) and the anthracycline resistance-associated gene (ARA), located within 9 kb of each other. Both genes are expressed in normal hematopoietic precursor cells and mediate resistance to a variety of chemotherapeutic agents. In a study of Kuss et al3 MRP1 deletions were found in five out of 13 (38%) AML patients with inv(16).3 Deletions were identified by fluorescence in situ hybridization (FISH) using a 3.8 kb sized cDNA probe representing parts of the MRP1 gene. Notably, the patients with the deletion had a significantly higher disease-free survival than those without the deletion. Based on these clinical data it was speculated that MRP1 deletion may be involved in the pathogenesis of AML with inv(16). The findings by Kuss et al3 could not be confirmed in two subsequent studies. In the FISH study by Marlton et al4 only six out of 42 (14%) AML cases with inv(16) were associated with 16p deletions using a cosmid contig as a probe. Furthermore, time to treatment failure was compared for the two patient groups and no difference was observed. Similar results were also reported in a study from Martinet et al.5 One drawback of all these studies is that the analyses were performed retrospectively in small series of patients treated heterogenously.

To prospectively evaluate the prognostic impact of MRP1 deletions in AML with inv(16) we analyzed 246 eligible AML patients treated within the German multicenter treatment trial AML HD93 conducted between 1993 and 1998. All patients received induction therapy consisting of two cycles of idarubicin, cytarabine (100 mg/m2), and etoposide (ICE), followed by first consolidation treatment with high-dose cytarabine (3 g/m2 × 6) and mitoxantrone (HAM). Patients with inv(16) were assigned to the low-risk arm of the study and obtained a second cycle HAM. Of the 246 patients, 25 had inv(16) as assessed by chromosome banding analysis and by FISH using the yeast artificial chromosome clone y854E2 spanning the p-arm breakpoint. Cases exhibiting inv(16) were subsequently analyzed for deletions at the p-arm breakpoint by interphase FISH using the five cosmids 46A12, zit14, zit18, 381F12, 66G12 which represent approximately 250 kb of genomic sequence containing MRP1.7 Four of the 25 (16%) cases exhibited a deletion encompassing MRP1. Twenty-three of the 25 patients with inv(16) achieved CR after two cycles of ICE; there were two early deaths. Three patients received allogeneic bone marrow transplantation as second consolidation therapy since these cases were initially diagnosed as having a normal karyotype but FISH retrospectively revealed inv(16). Thus, 20 patients were evaluated in an intention-to-treat analysis. There was no correlation between MRP1 deletion and remission duration. The median observation period was 43 months. Eight of 16 patients without and two of four patients with MRP1 deletion relapsed leading to an overall CR duration of 50% at 3 years.

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  1. Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany

    K Döhner, RF Schlenk & H Döhner

  2. Institute of Hematology, Erasmus University, Rotterdam, The Netherlands

    BA van der Reijden

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Döhner, K., Schlenk, R., van der Reijden, B. et al. Deletion of the multidrug resistance-associated protein (MRP1) gene in acute myeloid leukemia with inversion of chromosome 16 has no prognostic impact. Leukemia 14, 1154 (2000). https://doi.org/10.1038/sj.leu.2401804

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