FOXM1 is a therapeutic target for high-risk multiple myeloma

Abstract

The transcription factor forkhead box M1 (FOXM1) is a validated oncoprotein in solid cancers, but its role in malignant plasma cell tumors such as multiple myeloma (MM) is unknown. We analyzed publicly available MM datasets and found that overexpression of FOXM1 prognosticates inferior outcome in a subset (~15%) of newly diagnosed cases, particularly patients with high-risk disease based on global gene expression changes. Follow-up studies using human myeloma cell lines (HMCLs) as the principal experimental model system demonstrated that enforced expression of FOXM1 increased growth, survival and clonogenicity of myeloma cells, whereas knockdown of FOXM1 abolished these features. In agreement with that, constitutive up-regulation of FOXM1 promoted HMCL xenografts in laboratory mice, whereas inducible knockdown of FOXM1 led to growth inhibition. Expression of cyclin dependent kinase 6 (CDK6) and NIMA-related kinase 2 (NEK2) was co-regulated with FOXM1 in both HMCLs and myeloma patient samples, suggesting interaction of these 3 genes in a genetic network that may lend itself to targeting with small-drug inhibitors for new approaches to myeloma therapy and prevention. These results establish FOXM1 as high-risk myeloma gene and provide support for the design and testing of FOXM1-targeted therapies specifically for the FOXM1High subset of myeloma.

Replication stress and FOXM1 drive radiation induced genomic instability and cell transformation

“…6B). This activity is consistent with transgenic mice models showing that FOXM1 expression promotes early steps in tumorigenesis, promoting Clara cell and hepatocyte hyperplasia for example(69,70) and acting in conjunction with many other carcinogens (71) as well as cancer cell lines(72,73). Replication stress has been shown to be a source for genomic instability in pre-neoplasic lesions, while in normal cells replication stress leads to cell death or , as it reproduces many of the outcomes for RIGI reported in other model systems.…”

NEK2 Is an Effective Target for Cancer Therapy With Potential to Induce Regression of Multiple Human Malignancies

“…We reported that NEK2 is highly expressed in several cancer types, such as cholangiocarcinoma (22), breast (7, [23][24][25][26][27][28][29][30][31], colorectal (27,(32)(33)(34)(35), and pancreatic (36,37) cancer. Consistently, several researchers reported that high expression of NEK2 is identified in various cancer types, including testicular seminoma (27,38,39), cervical tumor (27), primary liver cancer (40), hepatocellular carcinoma (8, 41), prostate cancer (27,42), lung cancer (27,(43)(44)(45), ovarian cancer (46), renal cell cancer (47,48), myeloma (49), peripheral nerve sheath tumors (50), follicular lymphoma (51,52) and diffuse large B-cell lymphoma (52).…”

FOXM1 regulates leukemia stem cell quiescence and survival in MLL-rearranged AML

“…More recently, FOXM1 was shown to play a critical role in the maintenance of Glioblastoma stem cell 24 . FOXM1 upregulation was also observed in blood cancers including ALL 25 and myeloma 26 . Inhibition of FOXM1 reduced proliferation in AML leukemia cell lines 27 .…”