Proteasome subunit expression analysis and chemosensitivity in relapsed paediatric acute leukaemia patients receiving bortezomib-containing chemotherapy.
Drug combinations of the proteasome inhibitor bortezomib with cytotoxic chemotherapy are currently evaluated in phase 2 and 3 trials for the treatment of paediatric acute myeloid leukaemia (AML) and acute lymphocytic leukaemia (ALL).



We investigated whether expression ratios of immunoproteasome to constitutive proteasome in leukaemic cells correlated with response to bortezomib-containing re-induction chemotherapy in patients with relapsed and refractory acute leukaemia, enrolled in two Children's Oncology Group phase 2 trials of bortezomib for ALL (COG-AALL07P1) and AML (COG-AAML07P1). Expression of proteasome subunits was examined in 72 patient samples (ALL n = 60, AML n = 12) obtained before start of therapy. Statistical significance between groups was determined by Mann-Whitney U test.



Ratios of immunoproteasome to constitutive proteasome subunit expression were significantly higher in pre-B ALL cells than in AML cells for both β5i/β5 and β1i/β1 subunits (p = 0.004 and p < 0.001). These ratios correlated with therapy response in AML patients; β1i/β1 ratios were significantly higher (p = 0.028) between patients who did (n = 4) and did not reach complete remission (CR) (n = 8), although for β5i/β5 ratios, this did not reach significance. For ALL patients, the subunit ratios were also higher for patients who showed a good early response to therapy but this relation was not statistically significant. Overall, for this study, the patients were treated with combination therapy, so response was not only attributed to proteasome inhibition. Moreover, the leukaemic blast cells were not purified for these samples.



These first ex vivo results encourage further studies into relative proteasome subunit expression to improve proteasome inhibition-containing therapy and as a potential indicator of bortezomib response in acute leukaemia.
Department of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, The Netherlands.
Denise
D
Niewerth
Department of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, The Netherlands.
Gertjan J L
GJ
Kaspers
Department of Amsterdam Rheumatology & Immunology Center, VU University Medical Center, Amsterdam, The Netherlands.
Gerrit
G
Jansen
Department of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, The Netherlands.|Department of Hematology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.
Johan
J
van Meerloo
Department of Hematology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.
Sonja
S
Zweegman
Department of Pediatrics, Texas Children's Cancer and Hematology Centers, Baylor College of Medicine, Houston, TX, USA.
Gaye
G
Jenkins
Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Canada.
James A
JA
Whitlock
Department of Pediatrics, University of Colorado Health Sciences Center, Denver, CO, USA.
Stephen P
SP
Hunger
COG Operations Office, Arcadia, CA, USA.
Xiaomin
X
Lu
Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA.
Todd A
TA
Alonzo
Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands.
Peter M
PM
van de Ven
Department of Pediatrics, Texas Children's Cancer and Hematology Centers, Baylor College of Medicine, Houston, TX, USA.
Terzah M
TM
Horton
Department of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, The Netherlands. j.cloos@vumc.nl.|Department of Hematology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. j.cloos@vumc.nl.
Jacqueline
J
Cloos
D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D001706:Biopsy; D001800:Blood Specimen Collection; D000069286:Bortezomib / Q000008:administration & dosage* / Q000494:pharmacology; D002648:Child; D005260:Female; D006801:Humans; D007162:Immunoproteins / Q000032:analysis; D007223:Infant; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D011379:Prognosis; D046988:Proteasome Endopeptidase Complex / Q000032:analysis*; D061988:Proteasome Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D021122:Protein Subunits / Q000032:analysis; D012008:Recurrence; D016896:Treatment Outcome; D055815:Young Adult
D007162:Immunoproteins; D061988:Proteasome Inhibitors; D021122:Protein Subunits; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex
Bortezomib; Immunoproteasome; Pediatric acute leukaemia; Proteasome inhibitor