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Upregulation of FOXM1 in a subset of relapsed myeloma results in poor outcome

C. Gu,C. Holman,R. Sompallae,X. Jing,M. Tomasson,D. Hose,A. Seckinger,F. Zhan,G. Tricot,H. Goldschmidt,Ye Yang,S. Janz

Published 2018 in Blood Cancer Journal

ABSTRACT

Following up on our previous work demonstrating the involvement of the transcription factor, forkhead box M1 (FOXM1), in the biology and outcome of a high-risk subset of newly diagnosed multiple myeloma (nMM), we sought to determine whether upregulation of FOXM1 may also be a feature of relapsed myeloma (rMM). To that end, we analyzed the total therapy 2 (TT2) dataset (GSE2658) from the University of Arkansas for Medical Science, which contains microarray-based gene expression and clinical outcome data on 88 patients with known FOXM1 mRNA levels at baseline and relapse. Statistical comparison demonstrated a significant increase (p= 10) in mean (by ~70%) and median (~2.9-fold) FOXM1 expression upon relapse (Fig. 1a, left). Just like in nMM, the distinction between high and low FOXM1 message at relapse was of prognostic value: FOXM1 patients (n= 11, 12.5%) exhibited markedly reduced event-free survival and overall survival compared to FOXM1 patients (n = 77, Fig. 1a, right). To confirm these results with the help of an independent dataset that is more recent than TT2, we took advantage of myeloma patients from the University of Heidelberg, Germany, which were uniformly treated upfront using HDT/ASCT and new myeloma drugs. In this cohort of 692 patients with nMM, FOXM1 status was as negative a predictor of survival (Fig. 1b) as in the original study. Furthermore, relapsed myelomas from the Heidelberg cohort (n= 55) also demonstrated significant elevations of FOXM1 message compared to nMM (Fig. 1c, left) and FOXM1 status at relapse—found in 8 of 60 (13%) patients—led to an even more dramatic reduction in survival than seen in the TT2 cohort (Fig. 1c, right). These findings led us to conclude that upregulation of FOXM1 is a molecular marker of a subset of relapsed myelomas that results in inferior outcome in patients with peak expression levels. Because (1) FOXM1 is best known as positive regulator of cell cycle progression, (2) tumor cell proliferation is an important, independent, adverse determinant of myeloma patient survival and (3) myeloma relapse from chemotherapy ultimately results in selection of cell clones with increased proliferation rates, we decided to evaluate whether increased FOXM1 expression at relapse may be associated with increased myeloma proliferation. For this purpose, we relied on a validated gene expression-based proliferation index (GPI) of myeloma to stratify 712 patients with nMM and 82 patients with rMM from the Heidelberg cohort into three different groups defined by low, intermediate or high proliferation rates of tumor cells. Fig. 1d shows that FOXM1 expression paralleled the GPI score in both nMM (left panel) and rMM (right panel). High FOXM1 message levels, which even surpassed those measured in GPI myeloma, were also observed in normal plasmablasts derived from cytokineinduced peripheral blood B-lymphocytes of healthy donors and in rapidly dividing HMCLs (human myeloma cell lines) propagated in vitro (Fig. 1e). These results were consistent with the contention that FOXM1 regulates cell cycle progression in both normal and neoplastic plasma cells. Recurrent cancer including relapsed myeloma is frequently associated with therapy resistance acquired by changes in genetic pathways wherein FOXM1 has been repeatedly implicated. With this in mind, we asked

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