Die Rolle des Cereblon bindenden Proteins in der immunmodulatorischen Therapie des Multiplen Myeloms.

• Antragsteller: Professor Dr. Martin Kortüm
• Fachliche Zuordnung: Hämatologie, Onkologie ; Humangenetik
• Förderung: Förderung von 2012 bis 2015
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 224778962

• Erstellungsjahr: 2016

Zusammenfassung der Projektergebnisse

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.

Projektbezogene Publikationen (Auswahl)

• 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
  
• 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
  
• 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
  
• 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
  
• 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