Affiliation of authors: Department of Pediatric Oncology/Hematology, Charité Medical Center, Humboldt-University, Berlin, Germany
Correspondence to: Karl Seeger, MD, PhD, Department of Pediatric Oncology/Hematology, Charité Medical Center, Humboldt-University, Berlin, Germany (e-mail: karl.seeger{at}charite.de).
Moshynska et al. (1) recently reported the finding of somatic nucleotide insertions in the promoter region of the antiapoptotic myeloid cell leukemia 1 (MCL-1) gene in patients with chronic lymphocytic leukemia (CLL), giving a possible explanation of the mechanisms responsible for higher MCL-1 expression in these patients. The authors showed that these mutations were of prognostic significance in that they were associated with an adverse outcome in CLL patients.
MCL-1 is involved in the pathogenesis of hematopoietic malignancies and plays a critical role in the survival of malignant cells (2). Increased Mcl-1 protein levels are associated with progression to a more chemorefractory disease and, consequently, with clinical outcome in CLL (3,4), in adult acute myeloid leukemia (AML), and in adult acute lymphoblastic leukemia (ALL) (5).
To investigate whether MCL-1 promoter insertions also occur in relapsed childhood ALL and, if so, if they are of prognostic value, we sequenced the same region of the MCL-1 promoter from lymphoblasts in bone marrow samples of 134 children with first relapse of ALL, from nine cell lines (two B-cell precursor ALL lines [Reh and SUP-B15], six T-ALL lines [Loucy, Peer, HSB2, Jurkat, Molt4, and Molt16], and one Burkitt lymphoma line [Raji]), and from blood samples of six healthy control subjects. The 134 patients were enrolled in 2000 and 2001 in the relapse trials of the Berlin-Frankfurt-Münster Study group (ALL-REZ BFM), and their bone marrow samples were obtained after written informed consent. Statistical comparisons of characteristics of the 134 studied patients with those of 62 patients from whom leukemic samples were not available revealed no statistically significant differences, except that the group for whom samples were available had more patients with TEL/AML1-positive ALL (P = .018) and more patients of intermediate risk (S2) (P = .044). All patients were treated according to the protocol ALL-REZ BFM 96. Coincidence analyses of insertions with patient characteristics were performed using the Kruskal-Wallis test.
In bone marrow samples of 27 of the 134 patients and in Molt4 cells and the blood of one control subject, we found either a 6- or a 18-nucleotide insertion in the promoter region of the MCL-1 gene. We detected the same insertions in corresponding remission material that did not contain any leukemic cells from 12 of the 27 patients, indicating that the genetic alterations seem to be hereditary polymorphisms. Nineteen of the 27 patients were homozygous. The presence of an insertion was not associated with clinical outcome or with any of the known major prognostic parameters for outcome at relapse of ALL (Table 1).
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Thus, although MCL-1 promoter insertions also occur in childhood ALL with first relapse, these mutations are unlikely to contribute to the process of relapse and do not seem to have an independent prognostic influence in childhood ALL.
We also note that Tobin et al. (7) investigated the same promoter insertions of the MCL-1 gene in 173 CLL and 105 age-matched healthy controls. The insertions were detected in a much higher frequency in CLL patients (61%) and control subjects (69%) than we or Moshynska et al. observed. In contrast to the data presented by Moshynska et al., but in line with our data, no statistically significant differences in survival were shown between patients with or without an insertion.
REFERENCES
(1) Moshynska O, Sankaran K, Pahwa P, Saxena A. Prognostic significance of a short sequence insertion in the MCL-1 promoter in chronic lymphocytic leukemia. J Natl Cancer Inst 2004;96:67382.
(2) Michels J, Johnson PWM, Packham G. Mcl-1. Int J Biochem Cell Biol 2005;37:26771.[CrossRef][ISI][Medline]
(3) Saxena A, Viswanathan S, Moshynska O, Tandon P, Sankaran K, Sheridan DP. Mcl-1 and Bcl-2/Bax ratio are associated with treatment response but not with Rai stage in B-cell chronic lymphocytic leukemia. Am J Hematol 2004;75:2233.[CrossRef][ISI][Medline]
(4) Kitada S, Andersen J, Akar S, Zapata JM, Takayama S, Krajewski S, et al. Expression of apoptosis-regulating proteins in chronic lymphocytic leukemia: correlations with in vitro and in vivo chemoresponses. Blood 1998;91: 337989.
(5) Kaufmann S, Karp J, Svingen P, Krajewski S, Burke P, Gore S, et al. Elevated expression of the apoptotic regulator Mcl-1 at the time of leukemic relapse. Blood 1998;91:9911000.
(6) Seeger K, von Stackelberg A, Taube T, Buchwald D, Körner G, Suttorp M, et al. Relapse of TEL/AML1-positive acute lymphoblastic leukemia in childhood: a matched-pair analysis. J Clin Oncol 2001;19:318893.
(7) Tobin G, Skogsberg A, Thunberg U, Laurell A, Aleskog A, Merup M, et al. Mcl-1 gene promoter insertions do not correlate with disease outcome, stage, or VH gene mutation status in chronic lymphocytic leukaemia. Leukemia 2005;19:8713.[CrossRef][ISI][Medline]
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