William G. Schuett, Jr., Multiple Myeloma Research Laboratory

Our primary research interest concerns multiple myeloma, a neoplasm of terminally differentiated, immunoglobulin-producing B lymphocytes that reside in the hematopoietic bone marrow and are called plasma cells. We use genetically engineered mouse models of human myeloma as the principal experimental model system to elucidate mechanisms of malignant plasma cell development and evaluate new approaches to myeloma treatment and prevention. Working in close association with our clinical colleagues in the Division of Hematology and Oncology, we employ a bench-to-bedside-and-back strategy to translate laboratory advances to curing myeloma.

The laboratory is generously supported by an endowment in memory of William G. Schuett, Jr., a cancer advocate and business leader who lost his battle with myeloma after a long, heroic fight. The laboratory was established in 2018 and is directed by Dr. Siegfried Janz, the inaugural William G. Schuett, Jr., Multiple Myeloma Endowed Chair.

About the PI

After obtaining his medical degree and board certification in Clinical Immunology from the University of Leipzig, Germany, Siegfried Janz joined the Laboratory of Genetics at the National Cancer Institute (NCI), Bethesda, Maryland. He performed studies on the inflammation-dependent peritoneal plasmacytoma, the first-generation mouse model of human plasma cell neoplasms such as multiple myeloma, plasmacytoma and plasma cell leukemia. His tenure at NCI shaped an enduring fascination with fundamental and translational research into plasma cell malignancies.

In 2007 Janz joined the Department of Pathology at the University of Iowa (UI) Roy J. and Lucille A. Carver College of Medicine as a full research professor to conduct studies on second-generation mouse models of human myeloma dependent on deregulated expression of the cellular oncogene MYC (c-myc). This work took advantage of gene-insertion mice generated in the Janz Lab to mimic different fine structures of the human MYC-activating t(8;14)(q24;q32) translocation. As leader of the cancer genetics program, he was actively engaged in research efforts at the UI Holden Comprehensive Cancer Center.

In 2018 Janz relocated his laboratory to the Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin (MCW) Milwaukee, where he joined the Clinical Cancer Center and its Developmental Therapeutics Program. Janz currently works on an NCI-supported project (2R01CA151354), entitled “Biological validation of candidate myeloma genes,” that seeks to elucidate genetic pathways underlying malignant plasma cell transformation. Additionally, he serves as a subcontractor on a NCI project (1R01CA214246) directed by Dr. Alan Lichtenstein, UCLA, concerned with the mechanism by which the ribonucleoprotein hnRNP A1 regulates the translation of MYC message in myeloma cells.

View Dr. Janz publications

Lab Members

Fumou Sun, MS

Education: China Pharmaceutical University, PhD Microbial and Biochemical Pharmacy

Research: My MS and PhD training (defense scheduled 06/2019) were in the area of antibody engineering. I generated humanized and genetically engineered bispecific antibodies. Beginning in 2017, I have been developing expertise in multiple myeloma first at the University of Iowa and currently the Medical College of Wisconsin. Currently, I am carrying out studies on osteolytic lesions resembling human myeloma bone disease in transgenic mice. This project utilizes integrated 3D X-ray microscopy and µCT analysis to assess, for the first time, bone loss in plasma cell tumor-bearing mice in an objective, unbiased manner. I am also involved in ongoing studies on the biological validation of candidate myeloma drivers such as forkhead box M1 transcription factor, FOXM1.

Michael Pisano, BS

Education: Truman State University, BS Biology

Research: During my time in undergrad I learned basic RNA sequencing analysis in R language, worked on an epitope mapping project at A. T. Still University, and contributed to assay development as an R&D intern at Thermo Fisher Scientific, Carlsbad, CA. I joined the Janz lab at the University of Iowa as an Immunology graduate student in June 2017 and relocated in Fall 2018 to MCW where I hold a research appointment. My current project concerns genomic analysis of myeloma-like plasma cell tumors in a double-transgenic mouse model of human myeloma. To that end, I rely on next generation DNA and RNA sequencing, and proteomics. Of importance to my PhD dissertation project, I perform immunological studies including analysis of bone marrow infiltrating Th17 cells which have been implicated in myeloma bone disease.

Krista Lingle Mullen, BS

Education: Eastern New Mexico University, BS Anthropology, BS Forensic Science

Research: I joined the Janz lab as a MS student of pathology at the University of Iowa in Spring 2017. My thesis project is focused on genetic targeting of the transcription factor FOXM1 using CRISPR/Cas9 genome editing tools. The principle goal is to delete FOXM1 function in myeloma cell lines to elucidate pathways of FOXM1 dependent growth and survival. This will facilitate development of new FOXM1 targeted therapies for the treatment of high-risk multiple myeloma.

Yan Cheng, MS

Education: China Pharmaceutical University, MS Pharmacokinetics

Research: My PhD project in China (defense scheduled 06/2019) concerns the impact of psychological depression on prostate cancer progression. I found that sympathetic nerve activated FAK (focal adhesion kinase) in prostate cancer cells resulted in increased cancer invasion and tumor matrix remodeling. Also, I demonstrated that sympathetic activation induced neuropeptide Y (NPY) expression in prostate cancer cells attracted myeloid cell (Mo-MDSCs and macrophages) infiltration in the tumor and stimulated IL-6/STAT3 signaling in cancer cells. In April 2018 I joined the Janz Lab where I am currently using adoptive B cell transfer in the double transgenic IL6Myc mouse model of human myeloma to elucidate biological pathways of neoplastic plasma cell development. Besides FOXM1, this involves candidate genes identified in Michael’s genomic analysis described above. Additionally, I am developing projects studying the role of sympathetic nerve system and neural factors in multiple myeloma-a flagrantly understudied area of blood cancer research.

Current Research

Validation of forkhead box M1 (FOXM1) as a new therapeutic target in high-risk myeloma
Regulation of c-Myc proto-oncogene (MYC) translation by heterogeneous nuclear ribonucleoprotein A1 (HNRPA1)

Validation of forkhead box M1 (FOXM1) as a new therapeutic target in high-risk myeloma

Despite enormous progress in blood cancer research, the ability to treat and prevent multiple myeloma, the second most common hematologic cancer in the United States, remains severely limited. This is particularly true for the subset of patients diagnosed with high-risk myeloma. Addressing the current limitations requires research on the biological significance of candidate high-risk myeloma drivers, such as the transcription factor FOXM1. The main objective of our ongoing project is to elucidate the mechanism by which FOXM1 enhances the aggressiveness of myeloma. The central hypothesis is that FOXM1 affords a promising treatment opportunity for high-risk myeloma. Specific research aims include the assessment of the role of FOXM1 in myeloma biology (e.g., clonogenic growth and survival) and myeloma genetics (e.g., FOXM1 target genes and drug sensitivity). Also included is the determination of the role of FOXM1 in neoplastic plasma cell development, using genetically engineered mouse models of human myeloma as the principal experimental system. A specific objective of the in vivo studies is the correlation of the FOXM1 status of myeloma-like tumors in transgenic mice with the response to small-molecule FOXM1 and proteasome inhibitors. The long-term goal of the project is the development of new, targeted approaches to the treatment and prevention of myeloma.

Regulation of c-Myc proto-oncogene (MYC) translation by heterogeneous nuclear ribonucleoprotein A1 (HNRPA1)

The Janz Lab is a subcontractor for this project, which is directed by Dr. Alan Lichtenstein, UCLA. Its main objective is the development of a scientific rationale for the therapeutic targeting of the internal ribosome entry site (IRES) in the mRNA message of MYC, which effects cap-independent translation to MYC protein – a basic helix-loop-helix (bHLH) transcription factor important for many types of cancer including multiple myeloma. IRES-dependent MYC translation is particularly important for the survival of myeloma cells that undergo endoplasmic reticulum (ER) stress consequent to the unfolded protein response. Specific aims include the elucidation of the mechanism by which MAP kinase-interacting kinase (MNK), hnRNP A1 (HNRPA1) IRES transacting factor (ITAF), and ribosomal protein 25 (RPS25) mediate IRES function. Also included is the design and testing of small-compound inhibitors of IRES function for myeloma treatment. This will rely, in part, on genetically engineered mouse models (GEMMs) of human myeloma available in the Janz Lab. These models will also be used to determine the role of hnRNPA1-dependent IRES activity in the development and progression of myeloma-like neoplasms in mice. The long-term goal of the project is to target MYC protein synthesis for the treatment and prevention of multiple myeloma.

Contact Us

William G. Schuett, Jr., Multiple Myeloma Research Laboratory

(414) 955-5782

sjanz@mcw.edu