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with refractory disease may be more debilitated and unable to tolerate aggressive combination treatments. In contrast, patients with refractory disease may stand to benefit the greatest from combination therapy. Thus, should we abandon the use of single-agent therapy in favor of combinations in all settings? The data from Larocca et al1 clearly demonstrate the benefits of triple drug combinations, combining the old with the new, and it appears that this regimen both is more active than pomalidomide/ dexamethasone in lenalidomide-refractory patients and is well-tolerated. However, the patients, although lenalidomide-resistant, were less heavily pretreated overall (1-3 prior lines vs .5 for the Richardson study8). This difference in inherent drug exposure limits the ability to extrapolate the pomalidomide/ cyclophosphamide/prednisone data from Larocca to the generalized refractory myeloma patient population. The unanswered question remaining for the clinician is, who is this regimen best suited for? It appears that the pomalidomide/ cyclophosphamide/prednisone combination is effective and can be safely administered with very encouraging results. However, it remains unclear whether the benefits of combination therapy realized in early lines of therapy can be routinely applied to a sicker, less robust, refractory population after numerous lines of prior treatment. Until these types of trials are performed in the refractory relapse population, decisions regarding combination therapy, although they may be biologically appealing, need to be based on the physical and hematological reserve of the refractory patient in question. Thus, although the combination may be fortuitous, circumstances of an individual patient will dictate the ultimate utility and success of this approach. Conflict-of-interest disclosure: S.L. is a consultant for Millennium, Celgene, Novartis, BMS, Onyx, and Sanofi. n
4. Cavo M, Tacchetti P, Patriarca F, et al; GIMEMA Italian Myeloma Network. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010;376(9758): 2075-2085. 5. Garderet L, Iacobelli S, Moreau P, et al. Superiority of the triple combination of bortezomib-thalidomidedexamethasone over the dual combination of thalidomidedexamethasone in patients with multiple myeloma progressing or relapsing after autologous transplantation: the MMVAR/IFM 2005-04 Randomized Phase III Trial from the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. 2012;30(20):2475-2482. 6. Lonial S, Kaufman JL. The era of combination therapy in myeloma. J Clin Oncol. 2012;30(20):2434-2436.
7. Niesvizky R, Richardson PG, Rajkumar SV, et al. The relationship between quality of response and clinical benefit for patients treated on the bortezomib arm of the international, randomized, phase 3 APEX trial in relapsed multiple myeloma. Br J Haematol. 2008;143(1):46-53. 8. Richardson PG, Siegel DS, Vij R, et al. Randomized, open label phase 1/2 study of pomalidomide (POM) alone or in combination with low-dose dexamethasone (LoDex) in patients (Pts) with relapsed and refractory multiple myeloma who have received prior treatment that includes lenalidomide (LEN) and bortezomib (BORT): phase 2 results [abstract]. Blood. 2011;118(21):Abstract 634. 9. Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012;120(14):2817-2825. © 2013 by The American Society of Hematology
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Comment on Shukla et al, page 2848
IRF42/2Vh11 mice: a novel mouse model of CLL ----------------------------------------------------------------------------------------------------Yiming Zhong1 and John C. Byrd1
1
THE OHIO STATE UNIVERSITY
In this issue of Blood, Shukla and colleagues identify IRF42/2Vh11 mice, which develop spontaneous chronic lymphocytic leukemia (CLL) with 100% penetrance within 10 months as a novel mouse model of CLL, providing a new tool for investigating the pathogenesis of CLL and evaluating therapeutic agents.1
G
enetically modified mice are essential tools for investigating the roles of genes in development and progression of diseases and for preclinical testing of new therapies. The absence of good mouse models of CLL, the most common leukemia in Western countries, has hindered research and the development of therapies to combat this incurable disease. Due to the nonproliferating nature of circulating CLL cells, xenograft models of human CLL are inaccurate models of disease. In the last decade, several mouse models representing different subtypes of CLL have been developed. For
example, Em-TCL1 transgenic mice resemble aggressive CLL,2 Dlu2/miR15a/16-1 deletion mice3 and miR29b transgenic mice4 are related to indolent CLL, and TRAF2DN/Bcl2 double transgenic mice5 may be a model of refractory CLL. However, because of the complexity and heterogeneity of CLL and the limitations of current mouse models, the development of new mouse models of CLL is attractive. In this issue, Shukla and colleagues establish IRF42/2Vh11 mice as a novel mouse model of CLL with 100% penetrance within 10 months.1
REFERENCES 1. Larocca A, Montefusco V, Bringhen S, et al. Pomalidomide, cyclophosphamide, and prednisone for relapsed/refractory multiple myeloma: a multicenter phase 1/2 open label study. Blood. 2013;122(16):2799-2806. 2. Emadi A, Jones RJ, Brodsky RA. Cyclophosphamide and cancer: golden anniversary. Nat Rev Clin Oncol. 2009; 6(11):638-647. 3. Richardson PG, Siegel D, Baz R, et al. Phase 1 study of pomalidomide MTD, safety, and efficacy in patients with refractory multiple myeloma who have received lenalidomide and bortezomib. Blood. 2013;121(11):1961-1967.
Spontaneous CLL development in IRF42/2Vh11 mice. See Figure 1 in the article by Shukla et al that begins on page 2848.
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Interferon-regulatory factor 4 (IRF4) is a critical transcription factor for hematopoietic development and the immune system. It has been identified as an oncogene in multiple myeloma6 but a tumor suppressor in CLL.7 In this study, Shukla and colleagues backcrossed Vh11 mice which have a dramatically expanded B1 cell population into IRF4deficiency mice and found that 100% (n 5 12) of IRF42/2Vh11 mice developed CLL within 10 months (see figure). Among those IRF42/2Vh11 mice, 70% resemble indolent CLL and 30% exhibit aggressive CLL. Even after just 5 months, 7 of 12 (58%) IRF42/2Vh11 mice developed CLL and the rest developed monoclonal B-cell lymphocytosis (MBL). In contrast, no CLL or MBL was developed in the IRF41/1Vh11 control mice within 12 months. The authors also reported that IgM1CD51 CLL cells started to increase in the blood of IRF42/2Vh11 mice at 2 to 4 months of age and occupied ;69% of peripheral blood mononuclear cells at 8 months of age (see figure). IRF42/2Vh11 mice exhibited splenomegaly and lymph node enlargement and those with aggressive CLL had enlarged livers. The authors then identified the surface phenotype of IRF42/2Vh11 CLL cells as CD191, B220low/2, CD232, CD212, IgDlow, and CD1dint, and demonstrated that IRF42/2Vh11 CLL cells were transplantable in immunodeficient host mice. To further characterize the IRF42/2Vh11 CLL cells, Shukla and coworkers studied proliferation, survival, and molecular signatures of these cells and found that IRF42/2Vh11 CLL cells mainly proliferated in spleen while not in blood nor in lymph node, and these cells were resistant to apoptosis. Consistent with these findings, reexpression of IRF4 in IRF42/2Vh11 CLL cells in vitro promoted apoptosis. Very interestingly, the authors found that the expression of Mcl-1 which is a critical prosurvival factor for CLL cells8 was significantly increased in all 5 IRF42/2Vh11 CLL samples compared with controls, while the expression of TCL1 and miR15a/16-1 was not deregulated. Collectively, the findings in this study1 strongly indicate an important role of IRF4 in the initiation and progression of CLL and potential applications of this novel IRF42/2Vh11 mouse model in understanding CLL etiology and testing preclinical drugs.
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There are also several questions that need to be further addressed. First, in order to verify the role of IRF4 in the initiation of CLL, the transplantable ability of untransformed IRF42/2Vh11 cells should be further investigated. Second, IRF4 deficiency affects other lymphocyte subsets9; therefore, other potential abnormalities in IRF42/2Vh11 mice need to be characterized. Third, as the authors discussed in the manuscript, more generations of backcrossing are preferred to get a pure genetic background in IRF42/2Vh11 mice to further facilitate reproducibility of experiments. Overall, this study represents a significant step forward in our understanding of CLL, and the CLL field is looking forward to the applications of this new mouse model with respect to immunology, experimental therapeutics, and biology of this disease. Conflict-of-interest disclosure: The authors declare no competing financial interests. n REFERENCES 1. Shukla V, Ma S, Hardy RR, Joshi SS, Lu R. A role for IRF4 in the development of CLL. Blood. 2013;122(16):2848-2855.
2. Yan XJ, Albesiano E, Zanesi N, et al. B cell receptors in TCL1 transgenic mice resemble those of aggressive, treatment-resistant human chronic lymphocytic leukemia. Proc Natl Acad Sci USA. 2006;103(31):11713-11718. 3. Klein U, Lia M, Crespo M, et al. The DLEU2/miR15a/16-1 cluster controls B cell proliferation and its deletion leads to chronic lymphocytic leukemia. Cancer Cell. 2010;17(1):28-40. 4. Santanam U, Zanesi N, Efanov A, et al. Chronic lymphocytic leukemia modeled in mouse by targeted miR29 expression. Proc Natl Acad Sci USA. 2010;107(27): 12210-12215. 5. Zapata JM, Krajewska M, Morse HC III, Choi Y, Reed JC. TNF receptor-associated factor (TRAF) domain and Bcl-2 cooperate to induce small B cell lymphoma/chronic lymphocytic leukemia in transgenic mice. Proc Natl Acad Sci USA. 2004;101(47):16600-16605. 6. Shaffer AL, Emre NC, Lamy L, et al. IRF4 addiction in multiple myeloma. Nature. 2008;454(7201):226-231. 7. Chang CC, Lorek J, Sabath DE, et al. Expression of MUM1/IRF4 correlates with clinical outcome in patients with B-cell chronic lymphocytic leukemia. Blood. 2002; 100(13):4671-4675. 8. Pepper C, Lin TT, Pratt G, et al. Mcl-1 expression has in vitro and in vivo significance in chronic lymphocytic leukemia and is associated with other poor prognostic markers. Blood. 2008;112(9):3807-3817. 9. Mittru¨ cker HW, Matsuyama T, Grossman A, et al. Requirement for the transcription factor LSIRF/IRF4 for mature B and T lymphocyte function. Science. 1997; 275(5299):540-543. © 2013 by The American Society of Hematology
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Comment on Chaturvedi et al, page 2877
Targeting IDH: the next big thing in AML ----------------------------------------------------------------------------------------------------Mark Levis1
1
JOHNS HOPKINS UNIVERSITY
In this issue of Blood, Chaturvedi and coworkers use a small molecule inhibitor of mutant isocitrate dehydrogenase 1 (IDH1) to reverse the myeloproliferative effects induced by the “oncometabolite” 2-hydroxyglutarate (2-HG).1
J
ust occasionally, things in biomedical research actually work out the way they are supposed to. A few years back, groups of researchers all around the world began using next-generation sequencing techniques to sequence whole exomes and whole genomes from acute myeloid leukemia (AML) samples, a grand scheme that was supposed to identify new mutations that could be targeted with new therapeutics. One set of mutations emerging from these screens was found in genes encoding for the 2 isoforms IDH1 and IDH2. The mutations, first identified in gliomas,2 were noted to occur in 15% to 20%
of newly diagnosed AML patients, particularly in those with normal cytogenetics.3,4 After dusting off our biochemistry textbooks and reviewing the intermediates in the Krebs cycle, many of us in the field immediately wondered how such mutations could promote malignant transformation. Investigators who were not intimidated by a little biochemistry took up the challenge, and a clearer picture of how these new mutations promote transformation is now emerging.5-8 The IDH enzymes, as homodimers, convert isocitrate into a-ketoglutarate (a-KG), which turns out to be not only an intermediate in the
BLOOD, 17 OCTOBER 2013 x VOLUME 122, NUMBER 16
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
2013 122: 2769-2770 doi:10.1182/blood-2013-08-521120
IRF4−/−Vh11 mice: a novel mouse model of CLL Yiming Zhong and John C. Byrd
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