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From www.bloodjournal.org by guest on August 3, 2017. For personal use only. critical for hematopoietic effects. These studies caution against oversimplification in thinking about the likely complex paths from MLL to leukemia but further highlight the potential linkage to Hox genes and the power of genetic mouse models for investigating human disease. —Keith Humphries BC Cancer Agency 1. Ernst P, Wang J, Korsmeyer SJ. The role of MLL in hematopoiesis and leukemia. Curr Opin Hematol. 2002;9:282-287. 2. Buske C, Humphries RK. Homeobox genes in leukemogenesis. Int J Hematol. 2000;71:301-308. 3. Owens BM, Hawley RG. HOX and non-HOX homeobox genes in leukemic hematopoiesis. Stem Cells. 2002;20:364-379. 4. 5. CD4, although binding by multiple spikes could increase the avidity of binding.4 An alternative explanation is that once gp120 detaches, it has a high probability of reattaching to an adjacent CD4 molecule on the cell surface, producing the appearance of a long off-rate through a newly recognized phenomenon termed “allovalency.”5 (This explains the long-puzzling finding that soluble CD4 or anti-CD4 antibodies can prevent HIV infection even if added a few minutes after virion adsorption.) Eventually, of neutralizing antibodies is the likely evolutionary reason for this shuffling two-step at entry, then it would be interesting to know if a PDI-rearranged envelope is a better vaccine immunogen for raising neutralizing antibodies. PDI is too ubiquitous an enzyme to use as a drug target.6 However, just as drugs have been developed that block CD4 binding, chemokine coreceptor binding, and now, most successfully, gp41-mediated fusion, it will be interesting to learn if the PDI-rearrangement step in gp120 could provide a new therapeutic target. —Richard S. Kornbluth University of California, San Diego Lam DH, Aplan PD. NUP98 gene fusions in hematologic malignancies. Leukemia. 2001;15: 1689-1695. School of Medicine Ayton PM, Cleary ML. Transformation of myeloid progenitors by MLL oncoproteins is dependent on Hoxa7 and Hoxa9. Genes Dev. 2003;17:2298-2307. HIV envelope becomes unhinged by PDI for entry Almost 10 years ago, Ryser et al1 reported that cleavage of 2 disulfide bonds in the gp120 surface component of the HIV-1 envelope is required for virion entry into CD4-bearing cells and that cell surface protein disulfide isomerase (PDI) is responsible for this effect. Since that initial report, there have been numerous structural and mechanistic studies of envelope binding, yet exceedingly few of these studies have incorporated any model of dynamic changes in gp120 disulfide bonding. The notable exceptions are papers from Fenouillet et al2 and Barbouche et al3 that have confirmed the original Ryser et al findings. Now, in this issue of Blood, Markovic and colleagues (page 1586) weigh in as the third group to confirm these findings, and they provide new information about the location of PDI in previously undescribed domains of the cell membrane. The basic information is as follows: HIV virions, which bear perhaps only a dozen or so envelope spikes, use gp120 to bind to CD4, but this alone serves only to attach the virion loosely to the cell surface. Biophysical evaluation indicates that gp120 has a relatively short off-rate from monomeric BLOOD, 1 MARCH 2004 䡠 VOLUME 103, NUMBER 5 however, gp120 moves laterally along the membrane surface until it collides with a patch of PDI in a domain of the membrane that Markovic et al distinguish from a typical lipid raft. There, PDI reduces 2 disulfide bonds in gp120, producing conformation changes that likely stabilize the binding of gp120 to CD4 and expose the V3 loop for subsequent binding to the chemokine coreceptor. Following this, gp41 undergoes rearrangement into its fusigenic intermediates and entry occurs (Markovic and colleagues and Reyser et al,1 Fenouillet et al,2 Barbouche et al,3 and Gallina et al6). Taken in aggregate, the reports from these 3 groups have profound implications for our understanding of the HIV virion surface. As shown by Kwong et al,4 the relatively invariant CD4 binding site in gp120 is kept recessed to prevent access by otherwise neutralizing antibodies. The initial CD4 binding event is but a prelude to PDImediated reduction that unfolds the envelope into a more open conformation that presumably binds more favorably to CD4 and to the chemokine coreceptor. If evasion 1. Ryser HJ, Levy EM, Mandel R, DiSciullo GJ. Inhibition of human immunodeficiency virus infection by agents that interfere with thiol-disulfide interchange upon virus-receptor interaction. Proc Natl Acad Sci U S A. 1994;91:4559-4563. 2. Fenouillet E, Barbouche R, Courageot J, Miquelis R. The catalytic activity of protein disulfide isomerase is involved in human immunodeficiency virus envelope-mediated membrane fusion after CD4 cell binding. J Infect Dis. 2001; 183:744-752. 3. Barbouche R, Miquelis R, Jones IM, Fenouillet E. Protein-disulfide isomerase-mediated reduction of two disulfide bonds of HIV envelope glycoprotein 120 occurs post-CXCR4 binding and is required for fusion. J Biol Chem. 2003;278: 3131-3136. 4. Kwong PD, Doyle ML, Casper DJ, et al. HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites. Nature. 2002;420:678-682. 5. Klein P, Pawson T, Tyers M. Mathematical modeling suggests cooperative interactions between a disordered polyvalent ligand and a single receptor site. Curr Biol. 2003;13:1669-1678. 6. Gallina A, Hanley TM, Mandel R, et al. Inhibitors of protein-disulfide isomerase prevent cleavage of disulfide bonds in receptor-bound glycoprotein 120 and prevent HIV-1 entry. J Biol Chem. 2002; 277:50579-50588. Monoclonal antibodies in the treatment of chronic lymphocytic leukemia: if only it were simple The necessary condition to cure any malignancy is to achieve a complete response (CR), which for years has been extremely rare in chronic lymphocytic leukemia (CLL). Fortunately, the days in which treatment of CLL revolved around the use of 1567 From www.bloodjournal.org by guest on August 3, 2017. For personal use only. chlorambucil—an agent with which less than 10% CR was achieved—are over. Treatment of CLL has significantly improved over the last 2 decades. First, with the use of purine analogs, particularly fludarabine, the CR rate increased to 20% to 30%. Second, the combination of fludarabine with other cytotoxic agents and/or monoclonal antibodies has increased the CR rate up to 40% to 60%, with many of these responses being molecular (ie, without evidence of minimal residual disease as assessed by cytofluorometry or polymerase chain reaction [PCR]). Of note, there is already some indication that fludarabinebased regimens result not only in a higher CR but also longer response duration and, it is hoped, a prolonged survival.1,2 The 2 monoclonal antibodies most widely employed in CLL therapy are rituximab (an anti-CD20 monoclonal antibody that adds efficacy to chemotherapy) and alemtuzumab (an anti-CD52 agent that is particularly useful to improve responses obtained with chemotherapy). There are other monoclonal antibodies that offer promise in CLL treatment, including anti-CD22 (BL-22, epratuzumab), anti–HLA-DR (1D09C3), antiCD23 (IDEC-152, lumiliximab), and anti-1D10 (Hu1D10, apolizumab). The mechanism of action of monoclonal antibodies varies from one antibody to another and includes triggering of apoptosis by caspase-dependent or -independent pathways, antibody-dependent cellular cytotoxicity, complement-mediated cytotoxicity, and generation of reactive oxygen species (ROS).3 Things, however, are never simple. Mone and colleagues (page 1846) report in this issue a series of elegant studies showing that Hu1D10 has a paradoxical effect in CLL leukemic cells. Thus, Hu1D10 induces caspase-independent apoptosis and ROS generation (a desirable effect since it induces CLL leukemic cells’ death), but it also activates the AKT survival pathway (an undesirable effect since this protects leukemic cells from death). In other words, the same agent leads to both death and survival signals in CLL leukemic cells. To overcome the negative effect of AKT activation, the 1568 authors combine Hu1D10 with the selective phosphatidylinositol 3 (PI3) kinase inhibitor LY294002, leading to an enhanced activity of the antibody. This opens the door for clinical studies in which Hu1D10 will be combined with inhibitors of the AKT survival pathway such as UCN-01 (7-hydroxystaurosporine). Chemoimmunotherapy is gaining wide acceptance in the treatment of different oncohematologic disorders. What the Mone et al study illustrates is that mechanisms of action of monoclonal antibodies are complex and that when devising chemoimmunotherapy combinations, not only the different targets but also the mechanism of action of the agents, as well as the way to enhance their effects, should be considered. By pursuing this approach the CR rate in patients with CLL will continue to increase and, one hopes, this form of leukemia will eventually become curable. —Emili Montserrat University of Barcelona 1. Eichorst BF, Busch R, Hopfinger G, et al. Fludarabine plus cyclophosphamide (FC) induces higher remission rates and longer progression free survival than fludarabine (F) alone in first line therapy of advanced chronic lymphocytic leukemia (CLL): results of a phase III study (CLL4 protocol) of the German Study Group (GCLLSG) [abstract]. Blood. 2003;102:72a. Abstract 243. 2. Byrd JC, Rai KR, Peterson BL, et al. The addition of rituximab to fludarabine significantly improves progression-free and overall survival in previously untreated patients with chronic lymphocytic leukemia (CLL) patients. Blood. 2003;102:73a. Abstract 245. 3. Villamor N, Montserrat E, Colomer D. Mechanism of action and resistance to monoclonal antibody therapy. Semin Oncol. 2003;4:424-433. T-ALL: smoking guns and genes of interest Nonrandom chromosomal translocations are a common finding in the malignant cells of patients with acute and chronic leukemia. In general, these translocations lead to 1 of 2 molecular consequences. One class of translocation leads to the production of a fusion gene, such as the BCR-ABL oncoprotein associated with chronic myelogenous leukemia (CML); a second class of translocations leads to the unscheduled expression of a “proto-oncogene,” which is often a transcription factor involved in normal developmental regulation. This unscheduled expression of proto-oncogenes is most often caused by translocations that juxtapose regulatory regions of antigen receptor genes (immunoglobulin or T-cell receptor genes) and commonly involves transcription factors such as MYC, LMO2, or SCL (TAL1). Given that this second class of translocation involves antigen receptor genes, it is not surprising that translocations that activate proto-oncogenes are most commonly seen in lymphoid rather than myeloid leukemias. However, the same genes that are activated via chromosomal translocation can also be activated via unknown mechanisms. This is true for both human and mouse T-cell acute lymphoblastic leukemia (T-ALL).1,2 For instance, gene profiling studies have indicated that SCL and LMO1 or LMO2 are expressed in almost 50% of T-ALL patients. Furthermore, MSH2deficient mice, which frequently develop T-ALL, activate both SCL and LMO2. A “smoking gun,” in the form of a chromosomal rearrangement that juxtaposes an antigen receptor gene regulatory region with the proto-oncogene, can be identified in some of the T-ALL patients. However, in many patients—perhaps more than half—no such rearrangement can be found. There are at least 2 models that can be developed to explain this finding. The regulatory region of the proto-oncogene may have undergone a subtle mutation, leading to unscheduled, inappropriate activation of the protooncogene. Alternatively, a transcription factor that controls expression of the protooncogene may be inappropriately activated, leading to unscheduled expression of the proto-oncogene. These 2 models lead to a testable hypothesis. In the first case, expression of the proto-oncogene should be monoallelic; in the second case, expression of the proto-oncogene should be biallelic. In this issue, Ferrando and colleagues (page 1909) report their study of allelespecific expression of SCL, LMO2, and HOX11. As anticipated, in each case where there was a smoking gun, in the form of a BLOOD, 1 MARCH 2004 䡠 VOLUME 103, NUMBER 5 From www.bloodjournal.org by guest on August 3, 2017. For personal use only. 2004 103: 1567-1568 doi:10.1182/blood-2003-12-4387 Monoclonal antibodies in the treatment of chronic lymphocytic leukemia: if only it were simple Emili Montserrat Updated information and services can be found at: http://www.bloodjournal.org/content/103/5/1567.2.full.html Articles on similar topics can be found in the following Blood collections Information about reproducing this article in parts or in its entirety may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests Information about ordering reprints may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#reprints Information about subscriptions and ASH membership may be found online at: http://www.bloodjournal.org/site/subscriptions/index.xhtml Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. 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