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Expression of Polycomb-group (PcG) protein BMI-1 predicts prognosis in patients with acute myeloid leukemia

Leukemia volume 21, pages 1116–1122 (2007)Cite this article

BMI-1, a member of the Polycomb group of gene family, is essential for the self-renewal of hematopoietic, neural and cancerous stem cells.1 BMI-1 is highly expressed in malignancies like B cell non-Hodgkin lymphoma, Hodgkin's lymphoma, colorectal carcinoma, liver carcinoma, non-small cell lung cancer, breast carcinoma and medulloblastoma. Interestingly, the study of BMi-1 knockout mice revealed that BMi-1 is indispensable for the self-renewal of both leukemic and normal hematopoietic stem cells.2 In addition to its vital role in stem cell self-renewal, BMI-1 regulates the proliferative output of primitive hematopoietic progenitors in a critical manner.1 We reported previously BMI-1 as a marker of disease progression in cases of myelodysplastic syndrome (MDS).3 Therefore, we assumed that BMI-1 expression could be used to predict the prognosis of patients with acute myeloid leukemia (AML) and thus could serve as a tool to tailor therapy for this disease. This is the first study, in which flow cytometry was used to determine the expression of BMI-1 in AML blasts of human subjects.

We studied bone marrow (BM) samples (except two from peripheral blood (PB) and granulocytic sarcoma patient from the lymph node) obtained from 64 patients with newly diagnosed AML (Supplementary Tables 1 and 2). According to the Helsinki declaration, informed consent was obtained from the patients and donors (used as control), and an institutional review board approved the study. AML M3 patients were excluded from this study, due to their different disease biology and different treatment strategy. All cases of de novo AML were diagnosed as per the FAB criteria. Granulocytic sarcoma was diagnosed using lymph node biopsy. Secondary AML (MDS-AML or t-AML) was diagnosed according to the revised recommendations of the international working group on AML.4 Complete remission (CR), partial remission , overall survival (OS), relapse-free survival (RFS) and remission duration (RD) were defined as per recommendations of the same group.4 BM blasts ⩽5%, absolute neutrophil count ⩾1000 μl and platelet count ⩾100 000 μl were the criteria for CR. Cytogenetic remission or molecular remission was not used to define CR. Flow cytometry with appropriate antibody was performed to confirm the diagnosis and morphologic leukemia-free state. Survival was measured from the date of diagnosis to the date of death or last follow-up. To calculate cancer-specific survival (CSS), only deaths from the disease being studied were counted and treatment-related mortality was considered as an event. Also included in the evaluation were patients with reduced induction therapy owing to high age, poor performance status, comorbidity, etc. To facilitate comparison, we graded the standard dose of idarubicin (IDA) or daunorubicin (DNR) and cytosine arabinoside (Ara-C) as treatment intensity-3 (TI-3). High-dose Ara-C (HDAC, 2 g/m2 or more) or stem cell transplantation was considered as highly intensive therapy (TI-4). Sixty percent dose of Ara-C and IDA/DNR as treatment intensity-2 (TI-2) and less than this were stratified as treatment intensity-1 (TI-1). IDA 12 mg/m2 or DNR 50 mg/m2 and Ara-C 100 mg/m2 were considered as standard induction regimen, whereas IDA/DNR (the same dose as standard induction regimen) plus Ara-C 200 mg/m2 for three courses were considered standard consolidation regimen.

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Acknowledgements

We thank Dr Hideo Hyodo, Dr Hironori Harada, Dr Taiichi Kyo, Dr Hideo Tanaka, Dr Akira Sakai, for their help to collect patients’ sample. We also thank Nanae Nakaju, Sachiko Fukumoto, and Ryoko Matsumoto for their excellent technical support and Mohammad Doki for his help in data analysis.

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Authors and Affiliations

  1. Division of Clinical and Experimental Oncology, Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Minami-Ku, Hiroshima, Japan,

    M Chowdhury, K Mihara & A Kimura

  2. Division of Radiation and Regeneration Control, Department of Stem Cell Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Minami-Ku, Hiroshima, Japan,

    S Yasunaga & Y Takihara

  3. Division of Bio-Medical Informatics, Department of Environmetrics and Biometrics, Research Institute for Radiation Biology and Medicine, Hiroshima University, Minami-Ku, Hiroshima, Japan,

    M Ohtaki

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  1. M Chowdhury
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  2. K Mihara
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Correspondence to A Kimura.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Chowdhury, M., Mihara, K., Yasunaga, S. et al. Expression of Polycomb-group (PcG) protein BMI-1 predicts prognosis in patients with acute myeloid leukemia. Leukemia 21, 1116–1122 (2007). https://doi.org/10.1038/sj.leu.2404623

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