The role of Cereblon binding protein in immunomodulatory therapy of Multiple Myeloma.

• Applicant: Professor Dr. Martin Kortüm
• Subject Area: Hematology, Oncology ; Human Genetics
• Term: from 2012 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 224778962

• Final Report Year: 2016

Final Report Abstract

My research was focused on the genomic characterization of Multiple Myeloma with a focus on mutation screening in the key genes of the disease and the CRBN pathway, which is cruzial for the anti-MM action of the immunomodulatory drugs. Results obtained provided evidence of targetable mutations in MM as well as biomarkers of response and survival. Furthermore we described an altered mutational landscape of drug refractory disease, however this is still not fully understood and needs to be further explored. Apart from MM we identified recurrent mutations in chronic lymphocytic leukemia and described their role in disease progression and were first to describe the entire genome of a well-differentiated liposarcoma.

Publications

• Extramedullary myeloma whole genome sequencing reveals novel mutations in Cereblon, proteasome subunit G2 and the glucocorticoid receptor in multi drug resistant disease. Br J Haematol. 2013;161(5):748-751
  Egan JB, Kortuem KM, Kurdoglu A, Izatt T, Aldrich J, Reiman R, Phillips, L, Baker A, Shi CX, Schmidt J, Liang WS, Craig JD, Carpten JD, Stewart AK
  
• Genome-wide studies in multiple myeloma identify XPO1/CRM1 as a critical target validated using the selective nuclear export inhibitor KPT-276. Leukemia. 2013;27(12):2357-2365
  Schmidt J, Braggio E, Kortuem KM, Egan JB, Zhu YX, Shi CX, Tiedemann RE, Palmer SE, Garbitt VM, McCauley D, Kauffmann M, Shacham S, Chesi M, Bergsagel PM, Stewart AK
  
• Identification of cereblon-binding proteins and relationship with response and survival after IMiDs in multiple myeloma. Blood. 2014;124(4):536-545
  Zhu YX, Braggio E, Shi CX, Kortuem KM, Bruins LA, Schmidt JE, Chang XB, Langlais P, Luo M, Jedlowski P, LaPlant B, Laumann K, Fonseca R, Bergsagel PL, Mikhael J, Lacy M, Champion MD, Stewart AK
  (See online at https://doi.org/10.1182/blood-2014-02-557819)
• The clinical significance of cereblon expression in multiple myeloma. Leuk Res. 2014;38(1):23-28
  Schuster SR, Kortuem KM, Zhu YX, Braggio E, Shi CX, Bruins LA, Schmidt JE, Ahmann G, Kumar S, Rajkumar SV, Mikhael J, Laplant B, Champion MD, Laumann K, Barlogie B, Fonseca R, Bergsagel PL, Lacy M, Stewart AK
  (See online at https://doi.org/10.1016/j.leukres.2013.08.015)
• Ikaros degradation efficiency correlates with response of multiple myeloma (MM) cells to IMiD therapy and is blocked by proteasome inhibitors. Haematologica. 2015 May 14 [epub ahead of print]
  Shi CX, Kortuem KM, Zhu YX, Jedlowski P, Bruins L, Stewart AK
  
• Targeted sequencing using a 47 gene Multiple Myeloma Mutation Panel (M3P) in -17p high risk Disease. Br J Haematol. 2015;168(4):507-510
  Kortüm KM, Langer C, Monge J, Bruins L, Egan JB, Zhu YX, Shi CX, Jedlowski P, Schmidt J, Ojha J, Bullinger L, Liebisch P, Kull M, Champion MD, Van Wier S, Ahmann G, Rasche L, Knop S, Fonseca R, Einsele H, Stewart AK and Braggio E
  (See online at https://doi.org/10.1111/bjh.13171)
• Panel sequencing for clinically oriented variant screening and copy number detection in 142 untreated multiple myeloma patients. Blood Cancer J. 2016;6:e397
  Kortuem KM, Braggio E, Bruins L, Barrio S, Shi CS, Zhu YX, Tibes R, Viswanatha D, Votruba P, Ahmann G, Fonseca R, Jedlowski P, Schlam I, Kumar S, Bergsagel PL, Stewart AK
  (See online at https://doi.org/10.1038/bcj.2016.1)
• Genomic Characterization of High-Count MBL Cases Indicates that Early Detection of Driver Mutations and Subclonal Expansion are Predictors of Adverse Clinical Outcome. Leukemia; volume 31, pages 170–176 (2017)
  Barrio S, Shanafelt T, Ohja J, Chaffee K, Secreto C, Kortüm KM, Pathangey S, Van-Dyke Daniel, Slager S, Fonseca R, Kay N and Braggio E
  (See online at https://doi.org/10.1038/leu.2016.172)