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Editorials
2. Silver RT. Recombinant interferon-alpha for treatment of poly- cythaemia vera. Lancet. 1988;2(8607):403.
3. Gilbert HS. Long term treatment of myeloproliferative disease with interferon-alpha-2b: feasibility and efficacy. Cancer. 1998;83(6): 1205-1213.
4. Silver RT. Long-term effects of the treatment of polycythemia vera with recombinant interferon-alpha. Cancer. 2006;107(3):451-458.
5. Jones AV, Silver RT, Waghorn K, et al. Minimal molecular response
in polycythemia vera patients treated with imatinib or interferon
alpha. Blood. 2006;107(8):3339-3341.
6. Barbui T, Tefferi A, Vannucchi AM, et al. Philadelphia chromosome-
negative classical myeloproliferative neoplasms: revised manage- ment recommendations from European LeukemiaNet. Leukemia. 2018;32(5):1057-1069.
7. Silver RT, Kiladjian JJ, Hasselbalch HC. Interferon and the treatment of polycythemia vera, essential thrombocythemia and myelofibro- sis. Expert Rev Hem. 2013;6(1):49-58.
8. Kiladjian JJ, Cassinat B, Chevret S, et al. Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Blood. 2008;112(8):3065-3072.
Mysteries of partial dihydroorotate dehydrogenase inhibition and leukemia terminal differentiation
Yogen Saunthararajah
Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA E-mail: YOGEN SAUNTHARARAJAH - saunthy@ccf.org
doi:10.3324/haematol.2020.254482
It is reasonable to wonder why inhibiting dihydroorotate dehydrogenase (DHODH), a protean and vital metabol- ic enzyme, would be expected to solve, not exacerbate, prevalent oncotherapy problems of toxicity and resistance. Yet, in addition to ASLAN003, described in this issue of Haematologica,1 at least four other DHODH inhibitors are being developed for oncotherapy.2 DHODH is the sole mitochondrial enzyme in the pathway of de novo pyrimi- dine synthesis, which makes pyrimidine nucleobases from glutamine and aspartate. Pyrimidines are not just building blocks for DNA and RNA, but are also key cofactors for gly- coprotein, glycolipid and phospholipid synthesis. Moreover, the reaction that DHODH executes, reduction of dihydroorotate to orotate, is coupled to mitochondrial electron transport, to manufacture ATP independently of glucose and the Krebs cycle. Not surprisingly, therefore, DHODH is vital - its knock-out is lethal. Surprisingly, how- ever, treatment of malignant cells with clinically tolerable concentrations of DHODH inhibitors induces not the cyto- toxicity (apoptosis) expected from most anti-metabolite oncotherapeutics but terminal differentiation.
Unbiased analyses illustrate this: of the thousands of genes most significantly up- and down-regulated by ASLAN003 treatment of acute myeloid leukemia (AML) cells, most are the same genes coordinately up- and down- regulated during normal myeloid differentiation into granu- locytes or monocytes (Figure 1A). Such ready recapitulation of normal lineage progression is rendered less astonishing upon recognition that malignant cells express very high lev- els of lineage differentiation-driving master transcription factors to begin with, e.g., SPI1, CEBPA, RUNX1 in AML cells.3,4 One function of these lineage master transcription factors is to activate lineage differentiation programs, but another is to cooperate with MYC for high-grade activation of proliferation – coupling of exponential proliferation and onward differentiation in this way is a feature of metazoan
biology sometimes called ‘transit amplification’. Oncogenic
mutations decouple exponential proliferation from onward
4 differentiation to create malignant self-replication. In short,
partial DHODH inhibition reconnects circuitry already present to release malignant cells to complete lineage jour- neys already begun (Figure 1A).
This modality for leukemia/cancer cytoreduction is wor- thy of investment for three fundamental reasons. First, cell cycle exiting by terminal differentiation does not require the p53 apoptosis machinery that mediates cytoreduction by antimetabolite chemotherapeutics in general, and thus offers activity even in chemorefractory disease with p53- system mutations.4 Second, DHODH inhibitor-mediated induction of terminal differentiation is not restricted to rare AML or genetic subtypes of cancer, although differences in pyrimidine metabolism between histologically diverse can- cers may influence this activity (discussed below). Last but not least, non-cytotoxic differentiation-based oncotherapy can spare normal dividing cells essential for health/normal lifespan, offering a good therapeutic index.4 To efficiently realize these fundamentals in the clinic, however, an obvi- ous question needs an answer: how exactly does partial inhibition of DHODH, a protean metabolic enzyme, recon- nect cancer cells to terminal lineage fates intended by their master transcription factor content?
Given the contributions of DHODH and pyrimidines to so many fundamental cellular functions, it is difficult to know where to begin to answer this question. Fortunately, work spanning decades has provided excellent clues. One important observation is that the small molecule cyclopen- tenyl cytosine (CPEC), which inhibits the last step in de novo pyrimidine synthesis, uridine triphosphate (UTP) amina- tion into cytidine triphosphate (CTP) by CTP synthase 2 (CTPS2), also releases AML and solid tumor cancer cells to terminal lineage fates.5,6 Moreover, exogenous cytidine that restored CTP but not UTP pools, and exogenous uridine
9. Pizzi M, Silver RT, Barel AC, Orazi A. Recombinant interferon-a in myelofibrosis reduces bone marrow fibrosis, improves its morphol- ogy and is associated with clinical response. Mod. Pathol. 2015;28(10):1315-1323.
10. Silver RT, Barel AC, Lascu E, et al. The effect of initial molecular profile on response to recombinant interferon-a (rIFNa) treatment in early myelofibrosis. Cancer. 2017;123(14):2680-2687.
11. Mikkelsen SU, Kjaer L, Bjorn ME, et al. Safety and efficacy of com- bination therapy of interferon a-2 and ruxolitinib in polycythemia vera and myelofibrosis. Cancer Med. 2018;7(8):3571-3581.
12. Sørensen AL, Mikkelsen SU, Knudsen TA, et al. Ruxolitinib and interferon a2 combination therapy for patients with polycythemia vera or myelofibrosis: a phase II study. Haematologica. 2020;105(9): 2262-2272.
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