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Editorials
Ubiquitination is not omnipresent in myeloid leukemia
Ramesh C. Nayak1 and Jose A. Cancelas1,2
1Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center and 2Hoxworth Blood Center, University of Cincinnati Academic Health Center, Cincinnati, OH, USA
E-mail: JOSE A. CANCELAS - jose.cancelas@uc.edu / jose.cancelas@cchmc.org doi:10.3324/haematol.2019.224162
Chronic myelogenous leukemia (CML) is a clonal biphasic hematopoietic disorder most frequently caused by the expression of the BCR-ABL fusion protein. The expression of BCR-ABL fusion protein with constitutive and elevated tyrosine kinase activity is suffi- cient to induce transformation of hematopoietic stem cells (HSC) and the development of CML.1 Despite the introduction of tyrosine kinase inhibitors (TKI), the dis- ease may progress from a manageable chronic phase to a clinically challenging blast crisis phase with a poor prog- nosis,2 in which myeloid or lymphoid blasts fail to differ- entiate. Progression of BCR-ABL-positive (+) leukemia from the chronic phase to the acute blast crisis phase is accompanied by increased BCR-ABL expression and genomic instability leading to the acquisition of second- ary genetic lesions including +8, +Ph, +19, mutations in P53, Runx1, ASXL1, WT1TET2, IDH1, deletion of INK4A/ARF, and/or PAX5, IKZF1, EBF1 resulting in myeloid or B-lymphoid blast crises.3,4 However, our understanding of the mechanisms of transformation in blastic crisis remains incomplete.
In this issue of the Journal, Magistroni et al.5 identified the presence of mutations in three different amino acids (D144, I33, M34) impairing the expression and/or activity of one of the alleles of the ubiquitin conjugating enzyme E2A (UBE2A, also called RAD6A) in the blastic phase, but not in the chronic phase, of two out of ten CML patients. Analysis of an unmatched, larger cohort of 24 blast crisis, 41 chronic phase, 40 acute myeloid leukemia (AML), and 38 BCR-ABL-negative CML specimens confirmed the presence of these mutations in 16.7% of blastic phase CML patients but not in any of the other groups ana- lyzed. Mechanistically, the silencing of UBE2A or overex- pression of one of the UBE2A mutants (I33M) in BCR- ABL+ leukemic cells results in myeloid differentiation blockade in vitro with upregulation of ITGB4, RDH10 and CLEC11A, and downregulation of CFS3R/CSF3R and RAP1GAP. The fact that UBE2A mutations were exclu- sively found in the blast crisis CML patients, and these mutations control the process of differentiation arrest indicates that mutant UBE2A is a potential target for intervention in blastic phase CML.
Ubiquitin conjugating enzymes in inflammation and cancer
UBE2A is an E2 ubiquitin conjugating enzyme. Ubiquitination is a highly conserved post-translational modification process affecting the proteasome-mediated degradation as well as activity of target proteins. The process occurs in three sequential steps mediated by ubiquitin-activating enzyme (E1), ubiquitin conjugating enzyme (E2), and ubiquitin ligase (E3).6 In humans, near- ly 40 E2 ubiquitin conjugating enzymes regulate ubiqui-
tination of target proteins through their cognate E3 ubiq- uitin ligases belonging to three different families (RING,
7
HERCT, RING-between-RING or RBR type E3).
The ubiquitin conjugating enzymes including UBE2N (UBC13) and UBE2C are over-expressed in a myriad of tumors such as breast, pancreas, colon, prostate, lym- phoma, and ovarian carcinomas.8 Higher expression of UBE2A is associated with poor prognosis of hepatocellu- lar cancer.9 In leukemia, bone marrow (BM) cells from pediatric acute lymphoblastic patients show higher levels of UBE2Q2 expression in comparison to normal counter- parts.10 Ubiquitin conjugating enzyme E2E1 (UBE2E1) expression is adversely correlated with AML survival.11 However, in this report, the inactivating mutation of UBE2A seems to facilitate CML progression, and there-
fore UBE2A seems to act as a tumor suppressor.
Based on our understanding of mechanisms controlled by UBE2A, four different signaling pathways may be
involved in blast crisis transformation (Figure 1).
Inflammatory myeloid differentiation is mediated by ubiquitination
First, the abundance of pro-inflammatory cytokines including interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-a) in the leukemic microenvironment regu- lates myeloid differentiation through the activation of NFκB and MAPK signaling pathways.12 These activities are mediated by TNF-a receptor-associated factor (TRAF) family E3 ligases.13 The activation of IL-1 and TNF-a receptor induces the recruitment of MyD88, IL-1 recep- tor-associated kinase (IRAK4, IRAK2) to the myddosome complex resulting in the activation of TRAF6. UBE2A might act as upstream ubiquitin conjugating enzymes for TRAF6 E3 ligase in CML myeloid blasts, and loss-of-func- tion of UBE2A may attenuate the TRAF E3 ligase-mediat- ed activation of NFκB and MAPK signaling pathways, leading to the impaired myeloid differentiation (Figure 1, signaling path A). This is a signaling mechanism involved in myeloid differentiation with unclear significance in the context of UBE2A loss-of-function mutations.
Ubiquitination regulates BCR-ABL and MYC expression in myeloid leukemia
The transformation to blast crisis phase is associated with selection of clones with high BCR-ABL1 expression. However, the mechanism of enhanced BCR-ABL1 expression remains poorly understood. It has been shown that arseniate, a curative agent in acute promyelocytic leukemia, induced cell apoptosis and degradation of BCR- ABL in CML cells. The ubiquitination and degradation of BCR-ABL was mediated by c-CBL, a RING-type E3 ligase.14 Although speculative, it is possible that c-CBL acts as a cognate E3 ligase for UBE2A for the ubiquitina-
haematologica | 2019; 104(9)