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Editorials
and activates translesion synthesis DNA repair pathway.19 Furthermore, cell cycle dependent kinase-9 (CDK9) regu- lates UBE2A activity by phosphorylating at serine 120.20
UBE2A regulates the ubiquitination of histone H2B and proliferating cell nuclear antigen (PCNA) through the cog- nate E3 ubiquitin ligase RNF20/40 and RAD18, respec- tively. In addition to its role in transcriptional elongation, histone H2B K120 monoubiquitination plays a crucial role in DNA double strand break (DSB) repairs.21 Both these processes describe the role of UBE2A in DNA repair and maintenance of genome integrity. The loss-of-func- tion mutations of UBE2A in advanced phase CML patients may be associated with impaired ubiquitination of H2B and PCNA, and hence increased genome instabil- ity resulting in the acquisition of additional mutations (Figure 1, signaling paths C and D). The work by Magistroni et al.5 focuses on the latter signaling paths as possibly being at the root of the myeloid transformation. While the mechanisms that control the blastic transfor- mation of CML by UBE2A mutations remain unclear, mutation studies like that of Magistroni et al. do generate hypotheses that should be tested in further studies into BCR-ABL leukemia initiation and propagation.
References
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2. Gambacorti-Passerini CB, Gunby RH, Piazza R, Galietta A, Rostagno R, Scapozza L. Molecular mechanisms of resistance to imatinib in Philadelphia-chromosome-positive leukaemias. Lancet Oncol. 2003;4(2):75-85.
3. Perrotti D, Jamieson C, Goldman J, Skorski T. Chronic myeloid leukemia: mechanisms of blastic transformation. J Clin Invest. 2010;120(7):2254-2264.
4. Mullighan CG, Goorha S, Radtke I, et al. Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature. 2007;446(7137):758-764.
5. Magistroni V, Mauri M, D'Aliberti D, et al. De novo UBE2A muta- tions are recurrently acquired during chronic myeloid leukemia pro- gression and interfere with myeloid differentiation pathways.
Six-packed antibodies punch better
Christoph Rader1 and Adrian Wiestner2
Haematologica. 2019;104(9):1789-1797.
6. Swatek KN, Komander D. Ubiquitin modifications. Cell Res.
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9. ShenJD,FuSZ,JuLL,etal.Highexpressionofubiquitin-conjugating enzyme E2A predicts poor prognosis in hepatocellular carcinoma.
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UBE2Q2, a putative member of the ubiquitin-conjugating enzyme family in pediatric acute lymphoblastic leukemia. Arch Iran Med. 2012;15(6):352-355.
11. LuoH,QinY,ReuF,etal.Microarray-basedanalysisandclinicalval- idation identify ubiquitin-conjugating enzyme E2E1 (UBE2E1) as a prognostic factor in acute myeloid leukemia. J Hematol Oncol. 2016;9(1):125.
12. Anand M, Chodda SK, Parikh PM, Nadkarni JS. Abnormal levels of proinflammatory cytokines in serum and monocyte cultures from patients with chronic myeloid leukemia in different stages, and their role in prognosis. Hematol Oncol. 1998;16(4):143-154.
13. Barreyro L, Chlon TM, Starczynowski DT. Chronic immune response dysregulation in MDS pathogenesis. Blood. 2018;132(15): 1553-1560.
14. Mao JH, Sun XY, Liu JX, et al. As4S4 targets RING-type E3 ligase c- CBL to induce degradation of BCR-ABL in chronic myelogenous leukemia. Proc Natl Acad Sci U S A. 2010;107(50):21683-21688.
15. Reavie L, Buckley SM, Loizou E, et al. Regulation of c-Myc ubiquiti- nation controls chronic myelogenous leukemia initiation and pro- gression. Cancer Cell. 2013;23(3):362-375.
16. Bolton-Gillespie E, Schemionek M, Klein HU, et al. Genomic insta- bility may originate from imatinib-refractory chronic myeloid leukemia stem cells. Blood. 2013;121(20):4175-4183.
17. ShekharMP,LyakhovichA,VisscherDW,HengH,KondratN.Rad6 overexpression induces multinucleation, centrosome amplification, abnormal mitosis, aneuploidy, and transformation. Cancer Res. 2002;62(7):2115-2124.
18. Garg P, Burgers PM. Ubiquitinated proliferating cell nuclear antigen activates translesion DNA polymerases eta and REV1. Proc Natl Acad Sci U S A. 2005;102(51):18361-18366.
19. Hoege C, Pfander B, Moldovan GL, Pyrowolakis G, Jentsch S. RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO. Nature. 2002;419(51):135-141.
20. Shchebet A, Karpiuk O, Kremmer E, Eick D, Johnsen SA. Phosphorylation by cyclin-dependent kinase-9 controls ubiquitin- conjugating enzyme-2A function. Cell Cycle. 2012;11(11):2122- 2127.
21. Nakamura K, et al. Regulation of homologous recombination by RNF20-dependent H2B ubiquitination. Mol Cell. 2011;41(5):515- 528.
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1Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL and 2Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
E-mail: CHRISTOPH RADER - crader@scripps.edu ADRIAN WIESTNER - wiestnera@mail.nih.gov
doi:10.3324/haematol.2019.224196
In this issue of the Journal, Oostindie et al. investigate CD37-specific monoclonal antibodies (mAb) engi-
1
neered to undergo hexamerization. Efficient hexamer
formation is induced by a single amino acid substitution, E430G, in the IgG1 constant domain previously described by the same group.2 The modification potentiates com- plement-dependent cytotoxicity (CDC) against chronic lymphocytic leukemia (CLL) cells in vitro. Next, the authors show that combinations of hexamerization- enhanced mAb against CD20 and CD37 provide syner-
gistic activity. Intriguingly, the CD20- and CD37-target- ing mAb formed mixed hexameric complexes on the cell surface with increased anti-tumor activity.
The anti-CD20 mAb rituximab is a critical component of treatment regimens for many B-cell malignancies.3 In combination with chemotherapy, rituximab has been shown to increase response rates, response duration, and overall survival. Single-agent rituximab is quite common- ly used in follicular lymphoma and as maintenance ther- apy in several types of B-cell non-Hodgkin lymphoma (B-
haematologica | 2019; 104(9)