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`blood
`
`JOURNAL OF
`THE AMERICAN
`SOCIETY OF
`HEMATOLOGY
`
`Blood, Journal of The American Socicty of Hematology
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`SAN EX 1004,Page2
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`SAN EX 1004, Page 2
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`

`

`9 JUNE 2011 - VOLUME 117, NUMBER 23
`
`CONTENTS
`
`COVER FIGURE
`
`blood
`
`The cover image shows how maternal 1gG antibodies inhibit B-cell responses by
`cross-linking the B-cell receptor (BCR; membrane-boundIg in green in the center)
`with the inhibitory Fe receptor (FeyRIB; in brown on the left) through a measles
`vaccine yirus-IgG complex. This inhibition can be partially overcomebycross-
`linking the B-cell receptor with the stimulatory complement receptor 2
`(CD21/CD19/CD81/Leu-13; in green and blue to the right) through a measles
`vaccine virus—IgM (pentameterin purple)-complement C3d pratein (orange)
`complex. (IHustration by Tim Vojt, Medical Illustrator, The Ohio State University.)
`See thefull article by Kim et al on page 6143.
`INSIDE BLOOD
`SOCIETY OF
`
`INSIDEBLOOD
`
`JOURNAL OF
`THE AMERICAN
`
`HEMATOLOGY
`
`6057 Autografting CLL: the gameis over!
`E, Montserrat and J, G. Gribben
`
`6058
`
`A knockout for knockin
`L. O. Mosnier
`
`6060
`
`FVITI, CD4, and liaisons dangereuses
`M. V. Ragni
`
`6061
`
`‘T-cell depletion in GVHD: less is more?
`J. H.Antin
`
`PERSPECTIVES
`6063
`International Myeloma Working Group consensus approachto the treatment of
`multiple myeloma patients who are candidates for autologous stem cell
`;
`transplantation
`M.Cavo, S. ¥. Rajkumar, A, Palumbo,P. Moreau, R. Orlowski, J. Bladé, OQ. Sezer, H,Ludwig,
`M.A, Dimopoutos, M. Attal, P. Sonneveld, M. Boccadoro, K. C. Anderson, P. G. Richardson,
`W,Bensinger, H. E. Johnsen, N. Krocger, G. Gahrion, P. L. Bergsagel, D. H. Vesole, H. Einsele,
`S. Jagannath, R. Niesvizky, B. G. M. Durie, J. San Miguel, and S. Lonial, on behalfof the
`International Myeloma Working Group
`REVIEW ARTICLES
`6074
`Synthetic lethality: exploiting the addiction of cancer fo DNA repair
`M.Shaheen, C. Allen, J. A. Nickoloff, and R. Hromas
`
`6083
`
`~—_-Ex vivo expansion of human hematopoietic stem and progenitor cells
`A, Dahlberg, C. Delaney, and I. D. Bernstein
`
`HOW { TREAT
`
`6091
`
`6063
`
`CLINICAL TRIALS AND
`OBSERVATIONS
`
`HowI treat warfarin-associated coagulopathy in patients with intracerebral
`hemorrhage
`L. T, Goodnough and A. Shander
`
`
`
`.
`International Myeloma Working Group consensus approachto the treatment of
`multiple mycloma patients whoare candidates for autologous stem cell
`transplantation
`M.Cavo,S. ¥. Rajkumar, A, Palumbo,P. Moreau, R. Orlowski, J. Bladé, O. Sezer, H, Ludwig,
`M.A. Dimopoulos, M. Attal, P. Sonneveld, M. Boccadoro, K. C, Anderson, P, G, Richardson,
`W.Bensinger, H. E. Johnsen, N, Kroeger, G. Gahrion, P. L. Bergsagel, D. H. Vesole, H, Einscle,
`S. Jagannath, R. Niesvizky, B. G. M. Durie, J. San Miguel, and S. Lonial, on behalf of the
`International Mycloma Working Group
`
`ix
`
`BLOOD, 9 JUNE 2011 - VOLUME 117, NUMBER 23
`
`CONTINUED ON x
`
`SAN EX 1004,Page 3 _
`
`SAN EX 1004, Page 3
`
`

`

`
`
`_
`
`6074
`
`Synthetic lethality: exploiting the addiction of cancer to DNA repair
`M. Shaheen, C. Allen, J. A. Nickoloff, and R. Hromis
`
`6091
`
`How 1 treat warfarin-associated coagulopathy in patients with intracerebral
`hemorrhage
`L, T. Goodnough and A, Shander
`6100 HIV-1-related Hodgkin lymphomain the era of combination antiretroviral therapy:
`incidence andevolution of CD4* T-cell lymphocytes
`J. Bohlius, K. Schmidtin, F. Boud, G. Fatkenhcucr, M. May, A. M. Cary-Murillo, A. Mocralt,
`E. Bonnet, G. Clifford, V. Paparizos, J. M. Miro, N. Otel, M. Prins, G. Chéne, M. Egger, and
`Collaboration of Observational HIV Epidemiological Research Europe
`
`6109 Autologous stem cell transplantation as a first-line treatment strategy for chronic
`lymphocytic leukemia: 2 multicenter, randomized, controlled trial from the SFGM-
`TC and GFLLC
`L. Sutton, $. Chevret, O. Tourniihac, M. Diviné, V. Leblond, B. Corront, S, Leprétre, 1. Eghbali,
`E. Van Den Neste, M. Michalict, F. Maloisel, K. Bouabdallah, D, Decaudin, C. Berthou, P. Brice,
`#1, Gonzalez, E. Chapiro, 1, Radford-Weiss, N. Leporricr, K. Maloum, f% Nguyen-Khac, f. Davi.
`J, Lejeune, H, Merle-Béral, and M. Leporricr, for the Société Frangaise de Grelfe de Moelle et de
`Thérapie Cellulaire (SFGM-TC) and Groupe Frangais d'étude. de la Leucémic Lymphoide
`Chronique (GFLLC)
`
`6315 Briefreport Long-term risk for subsequent leukemiaafter treatment for
`childhood cancer: a report from the Childhood Cancer Survivor Study
`K. Nottage, J, Lanctot, Z. Li, J. P. Neglia, S. Bhatia, S. Hammond, W. Leisenring, A. Meadows,
`D. Srivastava, L. L. Robison, and G. T. Armstrong
`
`6367
`
`Incidenceof factor VIII inhibitors throughout life in severe
`Brief report
`hemophilia A in the United Kingdom
`C.R.M.Hay, B. Palmer, B. Chalmers, R. Liesner, R, Maclean, S. Rangarajan, M. Williams, and
`P. W. Collins, on behalf of United Kingdom Hacmophilia Centre Doctors’ Organisation
`(UKHCDO)
`
`6375 Chronic graft-versus-host disease: long-term results from a randomized trial on
`graft-versus-host disease prophylaxis with or without anti-T-cell globulin
`ATG-Fresenius
`G.Socié, C. Schmoor, W. A. Bethge, H. D. Oitinger, M. Stelljes, A. R. Zander, L. Volin,
`T. Ruuw, D.A, Heim, R. Schwerdtfeger, K. Kalbe, J. Mayer, J, A. Maertens, W. Linkesch,
`&, Holler, V. Koza, M. Bornhiiuser, H. Binscle, H.-J. Kolb, H. Bertz, M. Egger, O. Grishina, and
`J. Finke, for the ATG-Fresenius Trial Group
`
`6083
`
`6120
`
`vi
`ty
`Ex vivo expansion of human hematopoictic stem and progenitorcells
`A. Dahlberg, C, Delaney, and 1. D. Bernstein
`
`CDKGkinase activity is required for thymocyte development
`M. G, Hu, A. Deshpande, N. Schlichting, &. A. Hinds, C. Mao, M. Dose, G.-f. Hu,
`R.A. Van Etien, F. Gounari, and P. W. Hinds
`
`‘Three-dimensional imaging of whole midgestation murine embryos
`6132 Brief report
`showsan intravascularlocalization for all hematopoietic clusters
`T. Yokamizo, C. GL. Ng. M. Osato, and E, Dzierzak
`
`STAT3-dependent 1-21 production from Thelpercells regulates
`6198 Briefreport
`hematopoietic progenitor ecll homeostasis
`M. H. Kaplan, N. L. Glosson, G. L, Stritesky, N. Yeh, J. Kinzfog!, S. L. Rohrabaugh,
`R, Goswami, D. Pham, D. E. Levy, R. R. Drutkiewiez, J. S. Blum, S. Cooper, G. Hangoc, and
`1. £&. Braxmeyer
`
`HEMATOPOIESIS AND
`STEM CELLS
`
`x
`
`BLOOD,9 JUNE 2011 » VOLUME 117, NUMBER 23
`
`CONTINUED ONxii
`
`~ SANEX1004, Page co
`
`SAN EX 1004, Page 4
`
`

`

`IMMUNOBIOLOGY
`
`eee
`6120 - CDK6kinaseactivity is required for thymocyte development
`M.G, Hu, A. Deshpande, N, Schlichting, E, A, Hinds, C. Mao, M. Dose, G.-f. Hu,
`R. A. Van Etten, FE Gounari, and P, W. Hinds
`
`6135 Heat-shock protein 90 inhibition in autoimmunityto type VII collagen: evidence
`that nonmalignant plasmaeclls are not therapeutic targets
`M. Kasperkiewicz, R. Miller, R. Manz, M. Magens, C. M. Hammers, C. Somlai, J. Westermann,
`E. Schmidt, D. Zillikens, R. J. Ludwig, and A. Orosz
`
`8143
`
`Insights into the regulatory mechanism controlling the inhibition of vaceine-induced
`seroconversion by maternal antibodies
`D. Kim, D. Huey, M. Oglesbee, and S, Niewiesk
`
`6152 Advanced glycation end products of human Bz glycoprotein I modulate the
`maturation and function of DCs
`B. Buttari, E. Profumo, A. Capozzi, F. Facchiano, L. Saso, M.Sorice, and R. Rigand
`6162 Disruption of heparan sulfate proteoglycan conformation perturbs B-cell
`maturation and APRIL-mediated plasmacell survival
`R. M. Reijmers, R. W. J. Groen, A, Kuil, K. Weijer, F.C. Kimberley, J.P, Medema,
`T. H. van Kuppevelt, J.-P, Li, M. Spaargaren,and S. T. Pals
`
`6172
`
`6184
`
`142-3p in dendritic cells regulates endotoxin-induced
`
`‘Targeting of microRNA-
`mortality
`Y. Sun, S. Varambally, C. A, Maher,Q. Cao,P. Chockley, T, Toubai, C, Malter, E. Nieves,
`I. Tawara, Y. Wang, P. A. Ward, A, Chinnaiyan, and P. Reddy
`Efficientinfection, activation, and impairmentofpDCs in the BM and peripheral
`lymphoid organs during early HIY-1 infection in humanized rag2-/-y C-/- mice
`L. Zhang, Q.Jiang, G. Li, J. Jeffrey, G. 1, Kovalev, and L. Su
`
`6193 Brief report. NIIL3/E4BP4is a key transcription factor for CD8a+ dendritic cell
`development
`M. Kashiwada, N.-L. L. Pham, L, L. Pewe, J. T. Harty, and P. B. Rothman
`6198 Brief report
`STAT3-dependent IL-21 production from T helper cells regulates
`hematopoietic progenitorcell homeostasis
`M.H. Kaplan, N. L. Glosson, G. L. Stritesky, N. Yeh, J, Kinzfogl, S. L. Rohrabaugh,
`R, Goswami, D. Pham, D. B. Levy, R. R. Brutkiewicz, J, S, Blum, S. Cooper, G, Hangoc, and
`H. E. Broxmeyer
`
`6063
`
`International Mycloma Working Groupconsensusapproach to the treatmentof
`multiple myelomapatients who are candidates for autologous stem cell
`transplantation
`M.Cavo, 5, V. Rajkumar, A. Palumbo, P. Moreau, R. Orlowski, J. Bladé, O, Sezer, H. Ludwig,
`M. A. Dimopoulos, M. Attal, P. Sonneveld, M. Boccadoro, K. C, Anderson, P. G, Richardson,
`W. Bensinger, H. E. Johnsen, N. Kroeger, G. Gahrton, P. L. Bergsagel, D, H. Vesole, H. Binsele,
`5. Jagannath, R, Niesvizky, B. G. M. Durie, J. San Miguel, and S, Lonial, on behalfofthe
`International Myeloma Working Group
`6100 HIV-1-related Hodgkin lymphomain the era ofcombination antiretroviral therapy:
`incidence and evolution of CD4+ T-cell lymphocytes
`J. Bohtius, K. Schmidiin, F. Boué, G. Fatkenheuer, M. May, A. M. Caro-Murillo, A, Mocroft,
`F. Bonnet, G. Clifford, V, Paparizos, J, M. Miro, N. Obel, M.Prins, G. Chéne, M. Egger, and
`Collaboration of Observational HIV Epidemiological Research Europe
`
`LYMPHOID
`
`NEOPLASIA
`
`xii
`
`BLOOD,8 JUNE 2011 - VOLUME117, NUMBER 23
`
`
`CONTINUEDONxvi
`
`SANEX 1004, Page5
`
`SAN EX 1004, Page 5
`
`

`

`6109 Autologous stemcell transplantation as a first-line treatmentstrategy for chronic
`lymphocytic leukemia: a multicenter, randomized, controlled trial from the SFGM-
`TC and GFLLC
`L. Sutton, S. Chevret, ©. Tournithae, M. Diving, V. Leblond, B. Corrunt, §, Leprétre, H. Eghbali,
`E. Van Den Neste, M. Michallct, F. Maloisel, K. Bouabdallah, D. Decaudin, C. Berthou, P. Brice,
`H. Gonzalez, E. Chapiro, 1. Radford-Weiss, N. Leporricr, K. Maloum, F, Nguyen-Khae,F, Davi,
`J. Lejeune, H. Merle-Béral, and M. Leporrier, forthe Société Francaise de Greffe de Moelle et de
`Thérapie Cellulaire (SFGM-TC) and Groupe Frangais d’étude de la Leucémic Lymphoide
`Chronique (GFLLC)
`
`6202
`
`Integrin 87-mediated regulation of multiple myeloma cell adhesion, migration, and
`invasion
`P. Neri, L. Ren, A. K. Azab, M. Brentnall, K, Gratton, A, C. Klimawiez, C. Lin, P. Duggan,
`P. Tassane, A. Mansoor, D. A. Stewart, L. H. Boise, 1. M. Ghobrial, and N. J. Bahlis
`
`6214 Thesmall GTPase Racl is a novel binding partnerof Bel-2 andstabilizesits
`antiapoptotic activity
`R.Velaithan, J. Kang, J. L. Hirpara, T. Loh, B. C. Goh, M. Le Bras, C. Brenner, M.-Y, Clement,
`and 8, Pervaiz
`
`6227. Myc-medinted repression of microRNA-34a promotes high-grade transformationof
`B-cell lymphomaby dysregulation of FoxP1
`V.J. Craig, S. B. Cogliatti, J. Imig, C, Renner, S. Neuenschwander, H. Rehrauer, R, Schlapbach,
`S. Dimhofer, A. Tzankoy, and A. Miller
`
`6237. Constitutive activation of metalloproteinase ADAM10 in mantle cell lymphoma
`promotescell growth and activates the TNEo/NFKB pathway
`H. Armanious, P. Gelebart, M. Anand, A, Belch, and R. Lai
`
`6247
`
`Clonalorigins of relapse in ETV6-RUNXI acute lymphoblastic leukemia
`FW.van Delft, S. Horsley, $. Colman, K. Anderson, C, Bateman, H. Kempski, J. Zana,
`C. Eekert, V. Saha, L. Kearney, A. Ford, and M, Greaves
`
`6255 Combinatorial effects of microRNAs to suppress the Myc oncogenic pathway
`M.J. Bueno, M. Gomez de Cedrén, G. Gamez-Lépez,I. Pérez de Castro, L. Di Lisio,
`S, Montes-Moreno, N. Martinez, M, Guerrero, R. Sdnchez-Martinez, J. Santos, D. G. Pisano,
`M.A.Piris, J. Ferndndez-Piqueras, and M. Malumbres
`,
`
`6267 New markers for minimalresidual disease detection in acute lymphoblastic
`leukemia
`E. Coustan-Smith, G. Song, C. Clark, L. Key, P. Liu, M. Mehrpaoya,P. Stow, X. Su, S. Shurtleff,
`C.-EH, Pui, J. R, Downing, and D. Campana
`
`6277 Circulating human B lymphocytes are deficient in nucleotide excision repair and
`accumulate mutations upon proliferation
`N. Hyka-Nouspikel, K. Lemonidis, W.-T. Lu, and T, Nouspikel
`
`6287
`
`6297
`
`Brutontyrosine kinase represents a promising therapeutic target for treatment of
`chronic lymphocytic leukemia and is effectively targeted by PCI-32765
`S.E.M. Herman, A. L. Gordon, E, Herticin, A. Ramanunni, X. Zhang, S, Jaglowski, J, Flynn,
`J. Jones, K. A. Blum, J.J, Buggy, A. Hamdy, A. J. Johnson, andJ. C. Byrd
`
`Bortezomib induction of C/EBPB mediates Epstein-Barr viruslytic activation in
`Burkitt lymphoma
`C. M. Shirley, J, Chen, M. Shamay, H. Li, C, A. Zahnow,S. D, Hayward, and R, FL Ambinder
`
`MYELOID...=
`NEOPLASIA
`6074
`Synthetic lethality: exploiting the addiction of cancer to DNA repair
`M. Shaheen, C.Allen, J, A. Nickoloff, and R. Hromas
`
`xvi
`
`BLOOD, 9JUNE 2011 » VOLUME117, NUMBER 23
`
`CONTINUED ONxvil
`
`wo SANEX1004,Page6
`
`SAN EX 1004, Page 6
`
`

`

`6304
`
`Evi-1 is a transcriptional target of mixed-lineage leukemia oncoproteins in
`hematopoietic stem cells
`S. Arai, A. Yoshimi, M. Shimabe, M, Ichikawa, M. Nakagawa, Y. Inmi, 8. Goyama, and
`M., Kurokawa
`
`Long-termrisk for subsequent leukemia after treatment for
`6315 Briefreport
`childhood cancer: a report from the Childhood Cancer Survivor Study
`K, Nottage,J, Lanctot, Z. Li, J. P. Neglia, S, Bhatia, S, Hammond, W, Leisenring, A. Meadows,
`D.Srivastava, L. L. Robison, and G, T. Armstrong
`
`
`
`6355
`
`6319
`
`6347
`
`e207
`
`Platelet CD36 surface expressionlevels affect functional responses to oxidized LDL
`and are associated with inheritance of specific genetic polymorphisms
`A, Ghosh, G. Murugesun, K. Chen, L. Zhang, Q. Wang, M. Febbraio, R. M. Anselmo,
`K. Marchant, J. Barnard, and R. L. Silverstein
`
`Skeletal muscle hemojuvelin is dispensable for systemic iron homeostasis
`W.Chen, F. W. Huang,T. Barrientos de Renshaw, and N.C, Andrews
`
`Inhibition of antithrombin by Plasmodiumfalciparumhistidine-rich protein IT
`M. Ndonwi, O. O. Burlingame, A. S, Miller, D, M. Tollefsen, G. J. Broze Jr, and D. E. Goldberg
`
`e-Blood High-resolution genome-wide mappingof HIF-bindingsites by ChIP-seq
`J, Schédel, S. Oikonomopoulos, J. Ragoussis, C. W. Pugh, P. J. Ratcliffe, and D. R. Mole
`
`PLATELETS AND
`THROMBOPOIESIS
`
`RED CELLS,
`ERYTHronas
`
`THROMBOSISAND
`HEMOSTASIS
`6081
`How] treat warfarin-associated coagulopathy in patients with intracerebral
`hemorrhage
`L. T. Goodnough and A, Shander
`
`6326
`
`The developmentof inflammatory joint diseaseis attenuated in mice expressing the
`anticoagulant prothrombin mutant W215A/E2I17A
`M.J. Flick, A. K. Chauhan, M, Frederick, K, B. Talmage, K. W. Kombrinek, W. Miller,
`ES, Mullins, J, S. Palumbo, X. Zheng, N. L. Esmon, C. ‘T. Esmon, 8. Thornton, A. Becker,
`L.A. Pele, E. Di Cera, D, D. Wagner, and J. L. Degen
`
`6338 Activated protein C up-regulates procoagulant tissue factor activity on endothelial
`cells by shedding the TFPI Kunitz 1 domain
`R.A. Schuepbuch, K. Velez, and M, Riewald
`
`6347
`
`6355
`
`Inhibition of antithrombin by Plasmodiumfalciparum histidine-rich protein 1
`M. Ndonwi, O, O. Burlingame, A. S. Miller, D. M. Tollefsen, G. J. Broze Jr, and D. E, Goldberg
`
`Platelet CD36 surface expressionlevels affect functional responses to oxidized LDL
`andare associated withinheritance of specific genetic polymorphisms
`A. Ghosh, G. Murugesan, K. Chen, L. Zhang, Q, Wang, M. Febbraio, R. M, Anselmo,
`K, Marchant, J. Barnard, and R. L. Silverstein
`
`Incidence of factor VII inhibitors throughoutlife in severe
`6367. Brief report
`hemophilia A in the United Kingdom
`C.R.M.Hay, B. Palmer, B, Chalmers, R, Liesner, R. Maclean, S. Rangarajan, M. Williams, and
`P, W, Collins, on behalf of United KingdomHaemophilia Centre Doctors’ Organisation
`(UKHCDO)
`
`6371
`
`The antifibrinolytic functionof factor XIII is exclusively expressed
`Briefreport
`through oz-antiplasmin cross-linking
`S.R. Fraser, N. A. Booth, and N. J, Mutch
`
`xvii
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`BLOOD,9 JUNE 2011 - VOLUME 117, NUMBER 23
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`CONTINUED ON xvill
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`~~SANEX 1004;Page 7
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`
`
`TRANSFUSIONtcnt
`MEDICINE
`6091
`HowI treat warfarin-associated coagulopathy in patients with Intracerebral
`hemorrhage
`L, T. Goodnough and A. Shander
`
`TRANSPLANTATIONretiepprrere
`
`6063
`
`6375
`
`8383
`
`6392
`
`International Myeloma Working Group consensus approach to the treatmentof
`multiple mycloma patients who are candidates for autologous stem cell
`;
`transplantation
`M.Cavo, 8. V. Rajkumar, A, Palumbo, P. Moreau, R. Orlowski, J. Bladé, O, Sezer, H. Ludwig.
`M. A. Dimopoulos, M, Attal, P. Sonneveld, M. Boccadoro, K. C. Anderson, P. G. Richardson,
`W. Bensinger, H, E. Johnsen, N, Kroeger, G, Gahrton, P. L. Bergsagel, D, H. Vesole, H. Einsele,
`S. Jagannath, R. Niesvizky, B. G, M. Durie, J. San Miguel, and S. Loniat, on behalf of the
`International Myeloma Working Group
`
`Chronicgraft-versus-host disease: long-term results from a randomized trial on
`graft-versus-host disease prophylaxis with or without anti-T-cell globulin
`ATG-Fresenius
`G. Socié, C. Schmoor, W. A. Bethge, H. D. Ottinger, M.Stelljes, A. R. Zander, L. Volin,
`T. Ruutu, D. A, Heim, R, Schwerdtfeger, K. Kolbe, J, Mayer, J. A. Macrtens, W. Linkesch,
`E.Holler, V. Koza, M, Bornhiuser, H. Binsele, H.-J, Kolb, H. Bertz, M. Egger, O. Grishina, and
`J. Finke,for the ATG-Fresenius Trial Group
`
`Endothelial celt activation by antiphospholipid antibodies is modulated by Kriippel-
`like transcription factors
`K.L. Allen, A. Hamik, M. K.Jain, and K. R. McCrae
`
`Cholesterol sequestration by nystatin enhances the uptake and activity of endostatin
`in endothelium via regulating distinct endocytic pathways
`Y. Chen, §. Wang, X. Lu, H. Zhang, Y, Fu, and Y, Luo
`
`2207
`
`e-Blood High-resolution genome-wide mapping of HIF-bindingsites by ChIP-se¢
`J, Schidel, S. Oikonomopoutos,J, Ragoussis, C, W. Pugh, P, J. Ratcliffe, and D, R. Mole
`OTHER DEPARTMENTS
`xxxill Author Guide
`
`tvb
`
`Classifieds
`
`VASCULAR
`BIOLOGY
`
`SUBMISSION INSTRUCTIONS
`
`All manuscripts, includingfigures, should be submitted electronically at
`hitp://submit.bloodjournal.org to Editor-in-Chief Cynthia Dunbar, MD, Before submitting your
`paper, review Blood’s Author Guide at http:/Avww-.bloodjournalorg. If you need help during the
`submission process, contactthe Editorial Office by phoneat 202-776-0548 or via e-mail at
`editorial @hematology.org,
`
`xviii
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`BLOOD, 3 JUNE 2011 - VOLUME 117, NUMBER23
`
`i
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`“
`
`SANBX1004;Page 3
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`SAN EX 1004, Page 8
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`

`

`LYMPHOID NEOPLASIA
`
`
`
`Bruton tyrosine kinase represents a promising therapeutic target for treatment of
`chronic lymphocytic leukemia andis effectively targeted by PCI-32765
`Sarah E. M. Herman,!2 Amber L. Gordon,? Erin Hertlein,2 Asha Ramanunni,? Xiaoli Zhang,® Samantha Jaglowski,?
`Joseph Flynn? Jeffrey Jones,? Kristie A. Blum,? Joseph J. Buggy,* Anmed Hamdy,* “Amy J. Johnson,?* and “John C, Byrd?°
`‘Integrated Biomedical Science Graduate Program, The Ohio State University Medical Center, Columbus, OH; ?Division of Hematology, DepartmentofInternal
`Medicine and 3Centerfor Biostatistics, The Ohio State University, Columbus, OH; *Pharmacyclics Inc, Sunnyvale, CA; and SDivision of Medicinal Chemistry and
`Pharmacognosy, College of Pharmacy, The Ohio State Universily, Columbus, OH
`
`B-cell receptor (BCR) signaling is aber-
`rantly activated in chronic lymphocytic
`leukemia (CLL). Bruton tyrosine kinase
`(BTK) Is essential to BCR signaling and in
`knockout mouse models its mutation has
`a relatively B cell-specific phenotype.
`Hereln, we demonstrate that BTK protein
`and mRNAare significantly over ex-
`pressed in CLL compared with normal
`B cells. Although BTKis not always con-
`stitutively active in CLL cells, BCR or
`CD40 signaling Is accompanied by effec-
`
`Introduction
`
`PCI-32765inhibits activatlon-induced pro-
`tive activation of this pathway. Using the
`liferation of CLL cells in vitro, and effec-
`Irreversible BTK inhibitor PCI-32765, we
`tively blocks survival signals provided
`demonstrate modest apoptosis in CLL
`externally to CLL cells from the microen-
`cells that is greater than that observed in
`norma! B cells. No influence of PCI-32765
`vironment
`including soluble factors
`on T-cell survival is observed. Treatment
`(CD40L, BAFF, IL-6, IL-4, and TNF-.), fi-
`of CD40 or BCRactivated CLL cells with
`bronectin engagement, and stromalcell
`contact. Based on these collective data,
`PCI-32765 results in inhibition of BTK
`future efforts targeting BTK with theIrre-
`tyrosine phosphorylation and also effec-
`versible Inhibitor PCI-32765 in clinical tri-
`tively abrogates downstream survival
`als of CLL patients is warranted. (Blood.
`pathwaysactivated by this kinase includ-
`2011;117(23):6287-6296)
`ing ERK1/2, PI3K, and NF-«B. In addition,
`
`
`Chronic lymphocytic leukemia (CLL)is the most prevalent adult
`jJeukemia with an immunophenotype expressing the T-cell marker
`CD5together with CD19, CD20, CD23, and dim-surface immuno-
`globulin.! Although immunophenotypically similar to the normal
`BI lymphocytes, CLL cells have a distinct mRNA gene expression
`profile that most approximates a postgerminal memory B cell,? For
`many years CLL has been viewed as a nonproliferating leukemia
`based on the nonproliferating blood compartment; however, as
`with normal B cells, it has come to be recognized that CLL cell
`proliferation probably occurs in sites where microenvironmental
`stimulation occurs such as the lymph nodes and spleen, In such
`sites, proliferation centers are observed with a high proportion of
`dividing CLL cells expressing survivin that are often surrounded by
`either T cells or accessory stromal cells capable of providing
`cytokine costimulation.*4 Studies administering heavy water allow
`accurate measurementofall body compartments of CLL and assess
`the birth rate of CLL tumorcells in vivo.s These studies have
`demonstrated a broad rangeof proliferation of CLL cells that varies
`based on disease state and also immunoglobulin heavy chain
`variable (IVGH) mutational status,** In particular, a higher tumor
`birth rate is noted in CLL patients with IVGH unmutated disease
`and ZAP-70 expression. Multiple studies have documented evi-
`dence of enhanced B-cell receptor (BCR) signaling in patients with
`IVGH unmutated disease or those with increased ZAP-70 expres-
`sion.?9 Thus, accessory cytokines, cell-cell contact in the microen-
`vironment, and also BCR-signaling coupled to B-cell proliferation
`appearsentinel to CLL progression and pathogenesis.
`
`While understanding of CLL biology has improved dramati-
`cally, until very recently integration of these findings to treatment
`interventions has been lacking. Specifically, treatment has included
`alkylators, nucleoside analogs, and their combination where small
`advances in improved response and progression-free survival
`(PFS) have.been noted.!°!! However, these therapies have had very
`little impact on overall survival of CLL, The addition of the
`chimeric CD20 antibody, rituximab, perhaps represents the most
`significant advance in CLL therapy. Rituximab single agent
`activity’? and phase 2 studies combiningit with fludarabine (FR) or
`fludarabine and cyclophosphamide (FCR) have demonstrated im-
`provedoverall survival (OS) overhistorical controls,4!4 A random-
`ized trial of FCR versusfludarabine or cyclophosphamidealone
`demonstrated significant improvement in response; PFS and OS.
`While the presumptive mechanism ofrituximab in CLL has been
`assumedto be immunologic (reviewed in Jaglowski and Byrd"), a’
`recent study demonstrated a direct effect on BCR-signaling in both
`normal and malignant B cells via perturbation of membranerafts
`by CD20 antibody engagement.!? Given the survival benefit of
`rituximab as part of chemoimmunotherapy in CLL, this provides
`even more evidencefor therapeutics directed at BCR-signaling and
`the. proliferating component of CLL promoted by cytokines and
`cell-cell contact in the microenvironment.
`Targeting different components of the BCR pathway using
`pharmacologic agents can occur through a variety of different
`pathways including inhibition of proximal kinases such as Lyn,'5”
`Syk,202 and PI3K234 that each are constitutively active in CLL,
`
`Submitted January 2, 2011; accepted March 13, 2011. Prepublished online as Blood
`First Edition paper, March 21, 2011; DO! 10.1182/blood-2011-01-928484.
`
`The publication costs of this article were defrayed in part by page charge
`payment. Therefore, and solely ta indicate this fact,
`this article is hereby
`marked “advertisement”in accordancewith 18 USC section 1734.
`
`*A.J.J. and J.C.8,-are.senior authors and contributed equallyto this work.
`
`©2011 by The American Society of Hematology
`
`BLOOD,9 JUNE 2011 - VOLUME 117, NUMBER 23
`
`This material may be protected by Copyright law (Title 17 U.S. Code}
`
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`6288
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`HERMANetal
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`BLOOD, 9 JUNE 2011 * VOLUME 117, NUMBER 23
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`Inhibition of both Syk?! and the PI3K pathway** prevents CLL
`cells from interacting with the microenvironment andinhibition of
`Lyn,!® Syk2022 and PI3K?5 all promote proapoptotic signals.
`Clinical use of both the Syk inhibitor fostamatinib disodium’® and
`the PI3K-8 isoform specific inhibitor CAL-1017’ have shown
`clinical activity in refractory CLL. Giventhe success of therapeutic
`agents targeting BCR,
`identification of a proximal downstream
`kinase involved in both BCR and CLL proliferation induced by
`microenvironmental cytokines and cellular contact would offer the
`potential to deliver more selective therapy.
`Bruton tyrosine kinase (BTK) is a member of the Tec family
`kinases with a well-characterized role in BCR-signaling and B-cell
`activation. BTK is activated upstream by Src-family kinases and
`leads to downstream activation of essential cell survival pathways
`such as NF-kB and MAPK.Although BTKis expressed in multiple
`hematopoietic cells,
`the primary defect
`in knockout mice is
`B cell-specific, suggesting a more selective B-cell function. BTK
`mutations in humansgive rise to X-linked agammaglobulinemia,
`an inherited disorder that is characterized by severe B cell-specific
`defects including severely decreased levels of immunoglobulin
`production and the absence of B cells; further suggesting the
`importance andselectivity of BTK to B cells. BTK was recently
`identified in a siRNA screen as an essential kinase for survival in a
`subset of diffuse large-cell lymphomas driven by activated BCR
`where an irreversible BTK inhibitor, PCI-32765, was shown to
`promote. apoptosis.’ A second study of PCI-32765 recently noted
`in vivo clinical
`responses in dogs with aggressive B-cell
`lymphomas.”
`Based on the promise of BTK in aggressive lymphoma and the
`importance of BCR-signaling i