Martin Carroll

Author’s address Martin Carroll1 1 Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. Correspondence to: Martin Carroll University of Pennsylvania Room 708, BRB II/III 421 Curie Blvd. Philadelphia, PA 19104, USA Tel.: (215) 573-5217 Fax: (215) 573-7049 e-mail: [email protected] Acknowledgements Dr. Carroll is supported by NIH grants R21-CA-18536501, 5R01CA149566-04 and by the Leukemia and Lymphoma Society. Thanks to Terri M. Laufer for editing of the manuscript. The author has no relevant conflicts of interest to disclose.

This article introduces a series of reviews covering Hematologic Malignancies appearing in Volume 263 of Immunological Reviews.

Immunological Reviews 2015 Vol. 263: 2–4

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Immunological Reviews 0105-2896


When cancer and immunology meet

It is both exciting and challenging to assemble an issue of Immunological Reviews on hematologic malignancies in 2014. Both scientifically and clinically, the pace of advances has accelerated in the last few years. However, blood cancers remain a highly diverse group of diseases with many mechanisms of pathogenesis that require different clinical approaches. This diversity makes a comprehensive review of blood cancers a challenge. Instead, we have focused on in depth discussion of aspects of these topics that are either rapidly evolving or of particular interest to basic immunologists. The latter set of topics is itself diverse. Most blood cancers are themselves disruptions of the hematopoietic and immune systems. Some articles in this issue highlight the comparisons between normal immunologic development and the diseases that are associated with disruptions of immune development. A number of pieces focus on molecular mechanisms that are critical to both normal immunologic development and, when disturbed, cancer development. Others are focused on harnessing the immune system to treat blood cancers. This area has, in the last 2 years, achieved clinical responses that have long been sought (1, 2). A theme that runs through many of these reviews is the complexity of the immune system but the remarkable advances that years of research have made possible in both understanding biology and generating new therapies. Hematologic malignancies encompass the broad group of cancers that involve blood cells. Although individually these diseases are not the most frequent types of cancer, in composite the annual incidence of blood cancers in the United States is well over 100 000 cases per year based on recent review of the National Cancer Institute’s SEER data. Given that many people with blood cancers survive for many years, the number of Americans who are or have been impacted by blood cancers numbers in the millions. The blood cancers are usually classified as leukemias, lymphomas, myelomas, myeloproliferative neoplasms, and © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Immunological Reviews 263/2015

Carroll  When cancer and immunology meet

myelodysplastic diseases (MDS). However, as genetic classification of these diseases becomes commonplace, we are faced with challenges of nomenclature. Lymphomas are subdivided into over 40 different subclasses as described by phenotype and cell surface markers (1). The Cancer Genome Atlas project has described 23 genes that are recurrently mutated in acute myeloid leukemia (AML), not including the well-described chromosomal translocations that are associated with the disease. As molecularly targeted therapy becomes commonplace, it is likely that we will need to deal with nomenclature that sub-divides AML based on genetic abnormalities that predict prognosis or guide therapy. Thus, the division of this group of diseases into 5 sub-categories under-represents the complexity of blood cancers. Some of the recent advances in blood cancers are a direct result of the explosion in availability of DNA sequencing. As noted, the Cancer Genome Atlas project has already described novel genetic mutations in AML (2). Cooperative groups working with centers of excellence have described the genetics of pediatric acute lymphocytic leukemia (ALL) in great detail (3). Other groups have focused on multiple myeloma, adult T-cell ALL, and MDS (4–8). Importantly, these genetic explorations have revealed mutations in unexpected pathways stimulating entirely new areas of research. Suddenly, we are exploring concepts such as ribosomopathies, splicing defects, and the tumor microenvironment with new focus as genetic abnormalities reveal that these under-explored areas of biology are pathogenic for human diseases. Many of these areas were never previously hypothesized to have such roles. In this respect, the human genome project and the Cancer Genome Atlas have reaped large harvests for human health. Many themes emerge from these genetic studies, but one is currently ascendant in its impact on the field of hematologic malignancies. Epigenetics is progressing at an astounding speed and is the focus of reviews in this issue by Rao, Levine, Godley and Van Vlierberghe and their colleagues (9–12). Of these stories, one in particular bears summarizing. Just 5 years ago, Mardis et al. (13) and Yan et al. (14) described mutations in the Krebs cycle genes isocitrate dehydrogenase 1 and 2 in AML and glioblastoma. In that short period of time, investigators have demonstrated that mutated IDH1/2 generates an oncometabolite, 2-hydroxyglutarate (2HG) (15). This oncometabolite competes with a-ketoglutarate (aKG) for binding to the DNA-modifying enzymes of the TET family and disrupts TET function among other effects (16). Strikingly, TET2 was also identified as being recurrently mutated in AML (17). Thus, a © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Immunological Reviews 263/2015

major hypothesis in cancer biology, that cellular metabolism can influence gene expression, was demonstrated in a conclusive fashion (18). Most impressively, drug companies have already generated small molecules that specifically target mutant IDH, and early reports suggest that these drugs may have activity in patients with acute myeloid leukemia (c.f. Clinical NCT02074839). By contrast, the BCR/ABL oncogene, mutated in chronic myeloid leukemia (CML), was identified in 1984, and gaining an understanding of its biology to develop targeted therapies took 17 years. The pace of both discovery and therapeutic breakthroughs is accelerating. Many other important discoveries are highlighted in this volume. In July of this year, the US Food and Drug Administration granted breakthrough status to chimeric antigen receptor (CAR) T-cell therapy (19). The Novartis owned version of CAR T cells is now designated CTL019. As described in the review by Gill and June (20), this breakthrough required an extraordinary understanding of the life of a T cell. Designing a therapeutically effective antigen receptor construct required identification of the critical recognition sequences in immunoglobulins, the role (or lack thereof) of the major histocompatibility complex, and understanding of T-cell receptor and costimulationdependent signals. The clinical success of CAR T cells relied on rapid implementation of cytokine screens and the availability of drugs to block those cytokines to prevent fatal cytokine release syndromes. CAR T cells are still in their infancy, but the cure of children with relapsed acute lymphocytic leukemia reflects not only a victory for patient investigators around the world but a victory for the immunology community as a whole (19). As an example of ‘It takes a village’, we can think of no better example. Importantly, CAR T cells are only one example of the progress in immune therapies, as discussed by Nelson and Paulos (21). The diversity of blood diseases reflects both the complexity of the blood system and the diversity of molecular mechanisms that regulate blood cell development. Interestingly, different blood malignancies manifest as diseases of cells at different stages of hematopoietic differentiation. As described in the review of CML by Holyoake and Helgason (22), CML is a disease of hematopoietic stem cells (HSCs) and proliferating myeloid progenitors. In contrast, as reviewed by Inghirami et al. (23), T-cell lymphomas are a group of diseases that likely reflect blocks at multiple levels of T-cell differentiation from lymphoid precursors to T-follicular cells. Myeloma cells are terminally differentiated B


Carroll  When cancer and immunology meet

cells in some aspects but with a dependency on the marrow microenvironment not shared by normal plasma cells. This interaction is described here by Kawano et al. (24). Luckily, normal mammalian hematopoiesis and blood cancers share many features across species, allowing us to learn not only from studies of human diseases but from companion animals such as dogs, as reviewed by Richards and Suter (25). Regulating the complex process whereby HSCs proliferate to produce over 100 billion blood cells per day in adult humans producing multiple hematopoietic lineages requires fine tuning of a myriad of cellular processes. Some of these mechanisms are specific to blood cell development, such as disruptions of B-cell receptor signaling in lymphoma as reviewed by Buchner et al. (26). Others are cellular processes required by all eukaryotic cells and why their disruptions lead specifically to blood cancers is unclear. As described in other reviews, these include disrupted protein translation [reviewed by Osborne and Borden (27)], ubiquitin proteasome systems [reviewed in Sahasrabuddhe and Elenitoba (27) and Yang and Staudt 28, 29], and RNA splicing (reviewed by Hahn et al. 30). Overall, the study of blood cancers requires a broad understanding of both the cellular intricacies of hematopoiesis and a deep understand-

ing of how precisely ubiquitous cellular processes can be fine tuned for use by specific cellular lineages. Identifying genetic abnormalities in human cancers is advancing at a rapid pace. This in turn is increasing our knowledge of abnormal proteins generated by chromosomal abnormalities and mutations, leading to the question, ‘Can we turn off or regulate these oncogenes?’ The article by Cierpicki and Grembecka (31) on targeting protein–protein interactions through a combination of structural biology and high throughput screens demonstrates that increasingly, the answer is yes. There are significant barriers still to bringing small molecule and peptide inhibitors of protein–protein interactions into the clinic, but this review suggests that therapeutic use of such compounds is likely not far in the future. Although a large body of data is reviewed here, I am of the opinion that we have more to learn still than the sum of all that we have already learned. In that regard, it is to be hoped that these articles will not appear to present answered questions so much as unmet challenges. We hope that you enjoy these stories and continue to contribute to the understanding of blood cancer and further advances in the care of these often frightening and fatal diseases.

References 1. Campo E, et al. The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood 2011;117:5019–5032. 2. The Cancer Genome Atlas. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 2013;368:2059– 2074. 3. Mullighan CG, et al. Genomic analysis of the clonal origins of relapsed acute lymphoblastic leukemia. Science 2008;322:1377–1380. 4. Van Vlierberghe P, Ferrando A. The molecular basis of T cell acute lymphoblastic leukemia. J Clin Invest 2012;122:3398–3406. 5. Lohr JG, et al. Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy. Cancer Cell 2014;25:91–101. 6. Malcovati L, et al. Driver somatic mutations identify distinct disease entities within myeloid neoplasms with myelodysplasia. Blood 2014;124:1513–1521. 7. Haferlach T, et al. Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. Leukemia 2014;28:241–247. 8. Zhang J, et al. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature 2012;481:157–163. 9. Ko M, An J, Pastor WA, Koralov SB, Rajewsky K, Roa A. TET proteins and 5-methylcytosine oxidation in hematological cancers. Immunol Rev 2015;263:6–21.


10. Woods BA, Levine RL. The role of mutations in epigenetic regulators in myeloid malignancies. Immunol Rev 2015;263:22–35. 11. Moen EL, et al. New themes in the biological functions of 5-methylcytosine and 5-hydroxymethylcytosine. Immunol Rev 2015;263:36–49. 12. Peirs S, et al. Epigenetics in T-cell acute lymphoblastic leukemia. Immunol Rev 2015;263:50–67. 13. Mardis ER, et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med 2009;361:1058–1066. 14. Yan H, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med 2009;360:765–773. 15. Ward PS, et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 2010;17:225–234. 16. Figueroa ME, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 2010;18:553–567. 17. Abdel-Wahab O, et al. Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood 2009;114:144–147. 18. McCarthy N. Metabolism: unmasking an oncometabolite. Nat Rev Cancer 2012;12: 229.

19. Maude SL, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 2014;371:1507–1517. 20. Gill S, June CH. Going viral: chimeric antigen receptor T-cell therapy for hematological malignancies. Immunol Rev 2015;263: 68–89. 21. Nelson MH, Paulos CM. Novel immunotherapies for hematological malignancies. Immunol Rev 2015;263:90–105. 22. Holyoake TL, Helgason GV. Do we need more drugs for chronic myeloid leukemia? Immunol Rev 2015;263:106–123. 23. Inghirami G, Chan WC, Pileri S, AIRC 5xMille consortium ‘Genetics-driven targeted management of lymphoid malignancies’, The City of Hope Medical Center. Peripheral T-cell and NK cell lymphoproliferative disorders: cell of origin, clinical and pathological implications. Immunol Rev 2015;263:124–159. 24. Kawano Y, et al. Targeting the bone marrow microenvironment in multiple myeloma. Immunol Rev 2015;263:160–172. 25. Richards KL, Suter SE. Man’s best friend: what can pet dogs teach us about non-Hodgkin’s lymphoma? Immunol Rev 2015;263:173–191. 26. Buchner M, Swaminathan S, Chen Z, Muschen M. Mechanisms of pre-B-cell receptor checkpoint control and its oncogenic subversion in acute lymphoblastic leukemia. Immunol Rev 2015;263:192–209.

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Immunological Reviews 263/2015

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27. Osborne MJ, Borden KLB. The eukaryotic translation factor eIF4E in the nucleus taking the road less traveled. Immunol Rev 2015;263: 210–223. 28. Sahasrabuddhe AA, Elenitoba-Johnson KSJ. Role of the ubiquitin proteasome system in hematologic malignancies. Immunol Rev 2015;263:224–239.

29. Yang Y, Staudt LM. Protein ubiquitination in lymphoid malignancies. Immunol Rev 2015;263:240–256. 30. Hahn CN, Venugopal P, Scott HS, Hiwase DK. Splice factor mutations and alternative splicing as drivers of hematopoietic malignancy. Immunol Rev 2015;263:257–278.

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Immunological Reviews 263/2015

31. Cierpicki T. Grembecka. Targeting protein-protein interactions in hematologic malignancies: still a challenge or a great opportunity for future therapies? Immunol Rev 2015;263:279–301.


When cancer and immunology meet.

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