Blrmd
`
`JOURNAL OF
`
`THE AMERICAN
`
`SOCIETY OF
`
`HEMATOLOGY
`
`VOLUME 114
`
`NUMBER13
`
`4 SEPTEMBER 2009
`
`g5%
`
`l
`
`Allogenelc
`r"“"Splantatir.-n for
`CLL {p 2531]
`
`_"uantI-KIR antibody to
`gmant NK-mediatad
`killing (p 266?)
`
`D.
`
`aliffY-null leukopenic
`'ents With HIV have
`s""HII'thral advantage
`[p 2733)
`salac‘ive depletion
`. a”°reacttve 1' cells
`Ytheat Shock proteln
`arQEting (p 2329]
`
`:Yparfunctlonal C3
`_ Vertase and atypical
`_ Hus [p 2337)
`
`UNIV. CHICAGO EX. 2009
`
`I!
`PROPERTY OF THE
`an
`N!
`//fim\\§ NATIONAL
`LIBRARY OF
`MEDICINE
`
`32%?
`
`Genome & Co. v. Univ. of Chicago
`PGR2019-00002
`
`

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`

`blood4
`
`JOURNJIL OF
`
`THE AMERICAN
`
`SOCIETY OF
`
`HEMATOLDGY
`
`24 SEPTEMBER 2009 ‘ VOLUME 114. NUMBER 13
`
`CONTENTS
`
`COVER FIGURE
`
`It is unclear how neutrophils control xlspcrgillns species in healthy persons. Due to
`their large size. Aspcrgillm hyphae (red) cannot be plmgocytosetl by neutropllils
`(green). Bianelli et a] show in this issue that recently discovered NMWH
`oxirinse—dependent miernhicitlal pathways through neutropliil extracellular traps
`tNl‘I'I‘s} are efficient against x'ltspw'gfflttx conitlia and Ityphae in vitro. and that
`restoration ol' NET formation by gene therapy ol’ NADI’I-l oxidaseHlelicient
`X-Iinketl chronic grannlomatous disease aitletl clearing severe invasive Aspergillns
`nidnlam- inl'ection in vivo. underlining the role of functional NADNI ositlase in NET
`formation and antil'ungal activity. See the article by liianehi et al on page 261‘).
`
`INSIDE BLOOD
`
`2567 NR antilmtly the apy: KlR-ative intent
`N.S|1alu:|ntl IE. I. thall
`
`2558
`
`“'I‘as-ing" the cancer stem cell
`{ i. Fetter
`
`2569 Missteps in “tango" for epigenolne targeting
`K. I}. Robertson and K. N. BIL-Illa
`
`2570
`
`HIV: getting to the heart of IMRCness
`R. .I. I5. Nihl‘ns
`
`2571
`
`Platelet inlegrin signaling: wherefore art thon‘.’
`,\_ .-\, Schooner and M. 1.. Kuhn
`
`2572
`
`Super factor B-gets atypical IIUS
`Ii. M. Conway
`
`RERSPECTIVE
`
`2575
`
`Deli ning prior therapy in myelotlysplastic syndromes and criteria for relapsed and
`refractory disease: implications for clinical trial design and enrollment
`i\-1.r'\.5ekel'esanel I). I‘. Stccnsmtl
`
`REVIEW ARTICLE
`
`2581
`
`Allogeneie helnatopoietic cell transplantation for chronic lymphocytic leukemia:
`ready for prime time?
`.I. Delgado. I). W. Millignn. and I‘. ”regret
`
`CLINICAL TRIALS AND
`OBSERVATIONS
`
`2589
`
`Detailed analysis of pi} pathway defects in Iludarahine-rel'raclory chronic
`lymphocytie leukemia It‘ll): dissecting the contribution of I'lp deletion. ”’53
`mutation. |)53-le dysfunction. and IniR34a in a prospective clinical trial
`'l'.'/.eI1/. H. llill1c.'l'. Den/cl. .l. Mnhr. D. Winkler. .-\. lliihlet'. .-'\. Sumo. S. (irnncr. I). Mei-tens.
`
`R. lillscli.i\1. llaliek. ll. l)til1ncr.;1m1$.8Iilgcnhaucr
`
`ix
`
`BLOOD. 24 SEPTEMBER 2009 - VOLUME 114. NUMBER msmmrm “stoma
`a: the HLM and maybe
`Subject LlSCnpwight Laws
`
`CONTINUED ON I.
`
`

`

`2598 Determining the rise in BCR-Alil. RNA that optimally predicts a kinase domain
`mutation in patients with chronic myeloid leukemia on imatinib
`R. I). Press. 8. (L Willis. .l. Laududio. M. .l, Mauro. and M. W. N. IJeininger
`
`2506
`
`Donor, recipient. and transplant characteristics as risk factors alter unrelated donor
`I’llS(' transplantation: beneficial effects of higher (IDS-4+ cell dose
`M. A. l’tllxipher. P. ('hitphakdillmi. Ii. R. Logan. 5. I". Leilman. l’. Anderlini. .I.
`M. M. lllJI'l!Wl1.{..l. P. Miller. R. .l. Kings. and I). l.. ('nnl'er
`
`i’. Klein.
`
`2617
`
`Brief report The importance of bone marrow examination in determining
`complete response to therap}r in patients with multiple myeloma
`t‘. Ii. L'hce. S. Ktllllitl'. [)_ R. Larson. It. A. Kyle. A. Dispenxicri. M. A. {it-m. L‘.
`S. V. Rajltllnial'
`
`|.. Coin). and
`
`GENE THERAPY
`
`
`
`2619
`
`Brief report Restoration of NIC'I' formation by gene therapy in (1:1) controls
`aspergillosis
`M. Iiinnchi. A. lIaL‘kitn. V. Iirinknnlnn. ll. Siler. R. A. Sept-r. A. Kym-Idiom). and J. Rciehenbaeh
`
` IMMUNOBIOLOGY
`
`2523
`
`Dynamic accumulation of plasmacytoid dendl‘itic cells in lymph nodes is regulated
`by interferon-I5
`‘r'. tiao. Ii. i\«1a_ichrzak—Kila.
`
`I-I. N. Fish. and .I. l,. t'ionnnemuln
`
`2632 Mesenchymal stromal cells cross-present soluble exogenous antigens as part of their
`antigen-presenting cell properties
`M. Francois. R. Rt)llllL‘lt-h'1lltll'cl.S.Sttlclt-Nlttl'llltL‘tltl. M.-N. Iioivin. .I. l., Iiranlson. and
`.l. tialipeinl
`
`2639 Mast cells counteract regulatory 'l‘-eell suppression through interleukin-6 and
`()X4tii()X-'ltll.asis toward 'l‘I1I7-cell differentiation
`51'. l’ieoncsc, (i. (Iri. E'. 'l‘I'ii‘mdo. S. Musio. A. (lorraoelli. 8. mm. R. l’ctlolti. (.'.
`M. I’. t'olombo
`
`I-L. I’ucillo. and
`
`2649
`
`l’nenmm'iruses inl'ect eosinophils and elicit Myl)88-depemlent release of
`chemoattractant cytokines and interleukin-6
`K. I). Dyer. (‘. M. l’ereopo. Ii. R. Fischer. S. J. (iabrysmwski. and II. |-'. Rosenberg
`
`2657 Minimal requirement for induction of natural cytotoxicity and intersection of
`activation signals by inhibitory receptors
`Y. T. BryL'L’me.
`|'|.-(i. Lillnggren. and l5. U. Long
`
`2567
`
`Preclinical characterization of [-7 F9. a novel human anti~KlR receptor therapeutic
`antibody that augments natural killer—mediated killing of tumor cells
`l5. Romagné. l’. Andre. l’. Spec. 5. Kuhn. N. Animal. l.. t'iauthier. M. {'apanlll. |.. Rllpeeri.
`I). M. Benson .ir. B. W. lilascr, M. I}.('l1ics:t.A. Mm'eltn. li. Viricr. M. A. ('aligiln‘i. A. Vulm'tli.
`and N_ Wagtlnnnn
`
`3t
`
`BLOOD. 24 SEPTEMBER 2009 - VOLUME 114. NUMBEFl‘IlIlismaterialwascopied
`at the NLM and may be
`Subject USOnpvright Laws
`
`CONTINUED ON xi
`
`

`

`LYMPHOID
`
`
`_
`
`NEOPLASIA
`
`26?8 Mer receptor tyrosine kinase is a novel therapeutic target in pediatric B-cell acute
`lymphohlastie leukemia
`R. M. A. linger. I). Deltyckcic. |.. lirandau. K. K. .‘itlwclytl. K. M. Jueohsco. X. Liung.
`A. K. Renting. and I). K. (iruham
`
`2538 Dereguiated expression ol'cytokine receptor gene. (.‘RLFZ. is involved in lymphoid
`transformation in B-cell precursor acute Iymphohlastic leukemia
`l.. J. Russell. M. ('apusso. I. Valel'. 'I', Akusuku. t). A. Bernard. M. .i. (‘alasanL
`'I'. Chauidrasekaran. Ii. ('hupiro. S. (iesk. M. (iril'1iths. D. S. (iutlcry. C. |-|a|'erI'.1ch.l.. ilurder.
`f}.
`|-leidcnrcic|1.J. Irving. 1.. Kearney. I". Nguchi-Khae. l.. Macliado. l.. Minto. A. Majid.
`A. V. Moormnn. H. Morrison. V. Rand. J. (‘. .‘s'lrcl't'nrd. C. Schnah. I-I.
`'I'iinnics. M. .I. S. Dyer.
`R. Siehcrt. and C. J. l'larrison
`
`2699 Aurora kinase A is a target of Wntlflncatenin involved in multiple In yeloma disease
`progression
`J. UlttIa-Simnmns, ‘r’. Zinnia. (i. {iorguIL M. (kill. M. .'\-'l'.1|u,'l‘. l-lidcslnnlu. K. 'l'ais'ttiln.
`N. Ii. (‘arlstnL I). If. [‘al'rztscu. Y."l‘. 'l'ai. N. Rajc. A. (i. Lelai. K. (T. .*\Ildcrson. and
`I}. R. L’arrusco
`
`2709
`
`Identification of" cancer stem cells in a 'l'ax-transgcnie ('l‘ax-‘l‘gt mouse model of adult
`'l‘-cc|l leukemiai‘lvmphoma
`.1. ‘r'nmuzaki. 'I', Mixukumi. K. 'l‘nltixasv'a. M. Knrainilsu. I-I. Monime. A. Masumi. Y.:\I1Ii.
`
`II. llasegau'a. W. W. Hall. |-I.'|'stI_ii1I1qu. I.
`
`||annugucl1i.und K. ‘i'umnguchi
`
`2721
`
`'I‘herapeutic potential ol' an anti-(TD'F‘JI) antibody—drug conjugate. anti—Cl)79h-vc-
`MMAI‘Z. for the treatment of non—Hodgkin lymphoma
`I). Dot-nan. I". Bennett. Y.t‘l1e.n.:\'l. Dennis. I). Iialon. K. lilkins. I). French. M. A. 'I'. (in.
`A. Jack. J. R, .lunulula. tl. Kocppen. J. |.'.uI. J. Meliridc. A. Ran-stroll, X. Slu. N.YI1.S.vl:.YtI.
`l’. the. It. Klicng. A. lihcns.:1nti A. (i. Polson
`
`2730
`
`llriel' report A prospective study of serum soluble (1)30concentration and risk of
`non-I'lodgkin lymphoma
`M, I’. Purdue. If). l.:lll. (l. h-iill'tiilcr-Ma/u. M. M. ()kcn. W. Hocking. W.-‘i’. Iluung. I). iiaris.
`Ii.(‘0l1dc,und N. Rollimall
`
`MYELOID
`
`
`
`_
`
`NEOPLASIA
`
`2733
`
`(.‘omhined cpigcnetie therapy with the histone metllyltransl'erase ICZIIZ inhibitor
`3—deazaneplanoein A and the histone deacetylase inhibitor panohinostat against
`human AMl.cclls
`W. I’iskus. Y. Wang. A. Srccknmar. K. M. Buckley. 1|. Shi. A. .lilicllu. t'. Ustun. R. Ruo.
`l'. I-"crlnmtlex. .I. then. It. Italusn. 5. Koul. I’. Alailja. V. If. Marquez. and K. N. HhaIla
`
`2N4
`
`RUNX] regulates pllosphoinositidc J-kinaser'A K'l' pathway: role in chemotherapy
`sensitivity in acute megakaryocytic leukemia
`II. littu'ards. ('. Xic. K. M. Lal‘iora. A. A. IJoI11|1Lm\'sI\i.S.A. Huck. .l. l.. Itocrncl'. J. W. 'l‘uuh.
`
`I.. II. Malherly. and Y, (ie
`
`2753 Mutational spectru In at (iA'l‘Al prov ides insights into mulagcnesis and
`Ieukcmogenesis in Down syndrome
`I). ('. {‘ztl‘clnt'. II. V, l‘alcl. Q. ['hcn. II. will Remmen. 1.. it. Malherls. Y. ( ic. ilI'ILi .I. W. 'l‘nul'i
`
`II
`
`BLOOD. 24 SEPTEMBER 2009 - VOLUME 114. NUMBER-[fismterialwfitwied
`at the NLM and mavbe
`Subject LIE-Copyright La ws
`
`CONTINUED on In
`
`

`

`2764
`
`Early cpigenetic changes and DNA damage do not predict clinical response in an
`overlapping schedule of S—aaacytidinc and entinostat in patients with myeloid
`malignancies
`'I'. If.
`l-';IHLIy. J. (3. Herman. I’. Kerns. A. Jiemjil. l5. A. Sugar. S.-l-|. Chili. A. S. Yang. 'l‘. Aucull.
`'l'. Dames. R. ()dcllimar-Rcissig. J. l.lL'l'Il. M. .l. Mct‘mmcl]. t". Nasrallah. M. K. H. Kim.
`W. Klmng. Y. Sun. A. Margo. I.
`|ispilawn-Delgado. K. (Hello. I. Uwocyc. |.. R. Sifrermaln.
`5. I).{im'c.undIl.l-'..(‘an".1way
`
`PHAGOCYTES.
`
`
`
`GHANULOCYTES.AND
`MYELOPOIESIS
`
`2774
`
`.
`.
`'
`,. --.
`.,,..
`--
`a
`-
`.-
`‘
`hosmophll wahlllly Ir. Increased ll} acidic pH In .1 (AM!
`Inilnllcr
`
`.
`.
`§_
`;)
`)3.
`and f I R6. dependent
`
`l.. L'. Kntlyan. A. R. (’Isllicl'. K. H. Can. K. A. Niceic. M. lletlgchclh. ('. (i. Ruth]. 0. N. Willc.
`(l. K. Khurunu Ilcraliey. M. [3. Rollacnhcrg. and N. Zimmcrnmnn
`
`2783
`
`The Dufl'y-null state is assm‘iatcd with a survival advantage in leukopenic HIV--
`infected persons ol’Al‘rican ancestry
`II. Kulkm'ni. V. (‘. Marconi. W. Hc. M. l.. [.aminllu. J. F. Ukulica. J. lJulmnr. l). Kazululjitln.
`.I. (‘uslilllanctu S. S. Ahuja. l-'..
`.I. Wright. R. A. Wcisx. R. A. Clark. M. J, IJoIan. and S. K. Ahuja
`
`PLATELETS AND- _ _
`
`
`
`THROMBOPOIESIS
`
`2793 Distinct spatio-tcmporal (213+ signaling elicited by integrin uZL’tl anti glycoprotcin
`Vl under How
`
`M. Milnucaln. M. R. ('wfl. M. Htllli‘a‘llm. M. JtlllLll't‘l-I’L‘Tl'llh, M. Mnngial. l‘. Murchchc.
`'11]. Kunicki. K. M. Ruggcri. and I.. Dc Marco
`
`THHOMBOSIS AND_
`
`
`.
`
`HEMOSTASIS
`
`2802
`
`Enhanced et'licac}r of recombinant It‘Vlll in noncovalent complex with PICGyIatcd
`liposomc in hemophilia A mice
`J_ l’ulLl- Lin.J.-Y. KirI1.I).ZIIu.{‘. |-’utcl.7..-ll.("ui, X.7.I1;II15:.J.U. Ncw'prcn. A. Rcamcs.
`I). (‘unich (i. Jcsmnk. ti. 1“. Pierce. J. M. Summer. and H. Jim};
`
`2812
`
`'l‘llromhin induces the expression ol'oncostatin M via AP-l activation in human
`macrophages: :1 link between coagulation and inflammation
`5'.
`l’. Kaull. W. S.S|1L'ltll. K. M. Kitthtll’tw. C. Kaun. (i. Regal. A. Axsutlian. (I. W. llagmucllcl'.
`M. llncth. R. dc Marlin. Y. Ma. (i. Maorcr. K. Iluhcr. and .I. Wujlu
`
`2819
`
`A novel binding site for AIIAMTSI3 constitutively exposed on the surllicc of
`globular VWF
`S. Xanardelli. A. t". K. {’hiun. Ii. (irnul. l‘. J. Lenting. "I. A. J. McKinoun. M. A.
`M. Jimmy. and l). A. law:
`
`|.;I|l‘:ln.
`
`TRANSPLANTATION
`
`
`
`2829
`
`Selective depletion of alloreuctive 1' cells by targeted therapy of heat shock protein
`9": a novel strategy for control of gral't-versus-hoxt disease
`(1Stilt‘lilcl'.5.l\'liclkc. M.(.‘h:11lcricc.J. |)1|c|I.S. l.ur:lli. l". Rucckcrt. l-i. l‘linsclc. R. (I Baryon.
`and M. 5. 'I'npp
`
`xii
`
`BLOOD, 24 SEPTEMBEH 2009 - VOLUME 114. NUMBER lads marerIalwasc-upied
`at‘me NLM and may he
`Subject US Copyright Law;
`
`CONTINUED ON xiv
`
`

`

`VASCULAR BIOLOGY
`
`_
`
`2837
`llvperl‘unclional (73 con verlase leads to complemenl deposition on eudothellal cells
`and contributes to atypical hemolylic uremic syndrome
`|.. 'I'. Rounlcnintl. M. itihlonski, C. IILIL‘.
`.l. Hituiiil. l. I). llilltill'ov. |\-l.-r'\. Dragon-Dine};
`M. ('aylu. W. H. Fl'itlniao. M.—i’\. Mueller. I). Killers.
`|.. Moulongllel. |_. Ruslulng. S. C. Salehell.
`l’. W. Mntlueson. C. SauIes—liridmalr C. Loiratt. C. H. Regniur. |.. Halhu'uclis—ML‘L'arclli. and
`V. lirelnetiux—l'iiicel1i
`
`CORRESPONDENCE
`
`2846
`Role of TNFRSF 138 variants in patients with common variable immunodeficiency
`N. Martinez—Poona. N. Mutiuuoros. l). Dclkowi. i. I. Aroslegui. A. Alvarez. I’. Solcr-Pnlaelo. A.
`Vidalier. T. lispanol. A. Silinpalo. J. de Gracia. M. l-lernander. .I. Yaeiic. and N. Mutninoros
`
`2848
`
`Identification of monoclonal B-eell lymphocytosis among sibling transplant donors
`for chronic lymphocytic leukemia patients
`i. Del (lilitlicc. l‘. R. Mtlllrn. 31.8. De I’I'npl'is. l. l). Sltll'ru. l). Artnieltto. A. l’. lul'i. (i. I‘ernundu
`'l'orelli. A. (in:li'il1i.:ll1tl R.
`|-'ou
`
`2849
`
`The role ol'CBFB in AMlJ-E'I'O's activity
`5. Park. N. .-\. Speck, and .I. II. litlsllweller
`
`EFIFtATA
`
`
`2851
`Amhrogio et al. plfillCas mediates the transforming properties of the anaplastic
`lymphoma l-tinase. Blood. 2|Hl5:106[ 12):39l|7-39lfn,
`
`2851
`
`Nolte-‘t Hoen et al. Activated '1‘ cells recruit esosomes secreted by dendritie cells via
`LFA- 1. Blood. 2|I09:lI3t9}:1977-l98l.
`
`2852
`
`'l‘ni ct al. CSI promotes multiple myeloma cell adhesion. clouogcnie growth. and
`lunlorigenicity via t'-I11tIILntcdiated interaelions with hone marrow stronlal cells.
`Blood. 2009:] I 3[ 18}:430.‘J-43 18.
`
`OTHER DEPARTMENTS
`
`xxiii
`
`Author Guide
`
`iib
`
`Classifieds
`
`SUBMISSION INSTRUCTIONS
`
`All iminuscripts. including figures. should he sulmiitlcd electronically at
`htlp:tisuhrnit.l1Iootljournnlorg to liililor-in—(‘hiet't 'ynlllizi Dunbar. Ml). Ilel'ore submitting your
`pttliL't'. review Biomi'r Author (iuide Ell hllpflwwwhloodjtmrnulorg. ”you need help lllll‘lllg Ilie
`sulnnission process. contact the lidilorial ()l'liee by phone :Il 2i]2—77h~(l5-llt or via e-mail ill
`L'diltil‘iol(-7"lielllalolngyoi‘g.
`
`xiv
`
`BLOOD. 24 SEPTEMBER 2009 ' VOLUME “4. NUMBERflasi-naterial wasmpied
`att‘he NLM and mayr be
`Subject US Copyright Laws
`
`

`

`This material may be protected by Copyright law (Title 17 US. Code)
`
`
`IMMUNOBlOLOGY
`
`Preclinical characterization of l—7F9, a novel human anti—KlR receptor
`therapeutic antibody that augments natural killer—mediated killing of tumor cells
`
`Francois Flomagne.1 Pascale André.‘ Pieter Spec? Stefan Zahn? Nicolas Antossi.1 Laurent Gauthier,‘ Marusca Capanni?
`Loredana Ruggeri.3 Don M. Benson Jr.“ Bradley W. Blaser.‘1 Marietta Della Chiesa.5 Alessandro Morena.5 Eric Vivier.B
`Michael A. Caiigiuri.4 Andrea Velardifl and Nicolai Waglmann2
`
`1lnnate-Pbarma. Marseille. France; ZBiopharmacoulicals Research Unit. Novo Nordisk. Maaloev. Denmark: -'Deparlment of Clinical and Experimental Medicine.
`University oi Perugia. Perugia. Italy: "Ohio State University Comprehensive Cancer Center. Columbus; f‘i‘JipartImento di Medicina Sperimentale e Centro di
`Eccellenza per lo Flicerche Biomediche. Universila degli Studi di Genova, \i' is Benedetto XV. Genova. Italy: and "Centre d'lmmunologie de Marseille—Luminy.
`Universite de la Mediterranee. Inserm. Centre National de la Ftecherche Scientilique (CNFiS). Marseille. France
`
`inhibitory-cell killer immunoglobulin-like
`receptors (Kiri) negatively regulate natu-
`ral killer {NK} cell—mediated killing of HLA
`class l—expressing tumors. Lack oi KIR-
`HLA class I interactions has been associ-
`
`KIR2DL1. -2. and -3 receptors. and pre-
`vents their inhibitory signaling. The 1-?F9
`monoclonal antibody augmented NK cell—
`mediated lysis of HLA-c—expressing tu-
`mor cells.
`including autologous AML
`blasts. but did not induce killing of nor-
`mal peripheral blood mononuclear cells.
`suggesting a therapeutic window tor pret-
`erential enhancement of NK~cell cytotox-
`
`in
`an immunodeficient mouse model
`which inoculation of human NK cells
`
`alone was unable to protect against le-
`thal. autologous AML, preadministration
`of 1-?F9 resulted in long-term survival.
`These data show that 1-7F9 confers spe-
`cific, stable blockade of KIH. boosting
`NK-mediated killing of HLA-matched AML
`blasts in vitro and in vivo. providing a pre-
`clinical basis for initiating phase 1 clinical
`trials with this candidate therapeutic anti-
`body. (Blood. 2009;114:2667-2677}
`
`ated with potent NK-mediated antiturnor
`efficacy and increased survival in acute
`myeloid leukemia (AML) patients upon
`haploidentical stem cell transplantation
`from KlFl-mismatched donors. To exploit
`icity against malignant target cells. Admin-
`istration oi 1-7F9 to KlR20L3-transgenic
`this pathway pharmacologically, we gen-
`mice resulted in dose-dependent rejec-
`erated a fully human monoclonal anti-
`tion of HLA-CwS-positlve target cells. In
`body. 1-7F9, which cross-reacts with
`
`
`
`introduction
`
`few or no Ml-lC class i ligands for inhibitory receptors. Cancer
`cells that
`retain expression ol‘ class I molecules may evade
`NK—medialcd immunomrt’cillancc.“ Conversely.
`loss ol' MllC‘
`class I cspt'cssion renders tumor cells tnorc scnsilivc to killing
`by NK cclls. which may be associated with illlpl'ot'cd prognosis
`in some types ol‘ canccr. ’ “
`The human KIR l'atnily comprises polymorphic lg—likc mol-
`ecules expressed on NK cells. and small subsets of (138' and yF)‘
`‘1‘ cells.
`individual KIR bind distinct subgroups ol'
`lll..—\ class I
`:tllotypcs. and are clonally expressed in le'cclls. creating a
`repertoire ol' NK cclls \t'illl spccilicitics l'or dil'lct‘citl
`l'lLA class i
`moleculcs. KlRElfl. and KlRilll. have long cytoplasmic tails
`containing inhibitory signaling Inolil‘s. and 3 or 3 extracellular lg
`dol‘ttnins conl'cl‘l’ing spcciiicily l'or “LA-C or “LA-Alli allolypcs.
`i'espcctivcly. KIRZI'JIJ and KlRlllllfl recognize distinct l[[.t\—(‘
`itllntypcs. based on pol_\-'ntorphisins at positions 77 and lit} in the o1
`domain ol' the |-ll,r\ heavy chain.“ l-‘or example. KlRZl)l.l binds
`”LA—Cw}.
`-—i.
`-5. and ~(i. whereas K|l{2[)l.2 and —3 bind to
`
`Natural killer (NK) cells play critical roles iii host tlclcttse against
`infections and tumors. by secreting iInmunoregulatory cytokincs
`and by killing inl'cclcd or transformed cells. The activation ol'
`NK—ccll el'l‘ector
`functions is
`regulated by multiple types oi‘
`activating and inhibitory receptors that recognize ligands expressed
`on potential
`target cells.1 The balance between positive and
`negative signals transmitted via these NK receptors determines
`whether or not a target cell
`is killed by :In NK ccll.-‘ Activating
`receptors include NKpltl. NKp-l—l. NKplo. NKtlll). and llNAM- I.
`uinong otlicrs.‘ Their ligands appear preferentially on stressed.
`transformed. or infected cells. but not on normal. hculthy cellsi-‘L‘
`Tltetclol’c. transformed or inlet'lcd cclls may pi‘ot-‘idc activation
`signals and become sensitive to killing by NKcells. whereas
`healthy cells generally do not.) NK-cell expression of (‘lJlt’s the
`low—at'tinily l‘c receptor. provides an additional mechanism by
`which Nchlls may mediate antilumor el‘l‘ccts via antibody—
`dcpcndenl cellular cytotoxicily tAl)(‘(‘i toward anobody—coated
`target cells. Signaling through activating NK receptors is nega-
`tively regulated vial inhibitory receptors. such as killer immuno—
`glohulin [lgl—likc receptors tKlRi. (‘D‘J—UNKGZA. and leukocyte
`lg-like receptor-l. which recognize major hislocotnpalihility
`complex {Ml-K‘i—chtss l molecules. l-Ll‘licient NK cell -tncdiaicd
`killing occurs when target cells abundantly esprcss stress— or
`Irunsl‘ortnation-induced ligands for activating NK receptors. and
`
`
`[lift—Cw l . -_l. —7. and -t<, (‘ollcctivcly the inhibitory KlRll)l .l. 51.
`nitd —3
`I'cccptors rccognixc essentially till
`llllA-{f :tllolypcs‘.
`In
`contrast to Kll'IZDL receptors. KlRlllfi and KIIUIJS have short
`cytoplasmic tails with activating polcnlinl. "
`NK cells may cocxpi’css intllliplc inhibitor}r KIRs. nndt’or other
`Ml-l(' class l--specilic inhibitory receptors with dil'lcrcnt Mllt'
`
`Submitted February 23. 2009: accepted June 15. 2009. Prepublished online as
`Blood First Edition paper. June 24. 2009: DOI 1t). It82rb|ood-2009-02-206532.
`
`An Inside Blood analysis oi this article appears at the Iront of this issue.
`
`The publication costs of this article were delrayed in part by page charge
`payment. Therelore. and solely to indicate this fact.
`this article is hereby
`marked "advertisement" in accordance wan to USC section NM.
`
`The online version of this article contains a data supplement.
`
`(5:) 2009 by The American Society oi Hematology
`
`BLOOD. 24 SEPTEMBER 2009 - VOLUME 11<I,NUMBEl-t 13
`
`This mater-i at was copied
`at the NLM and may be
`Subject US Copyright Laws
`
`266?
`
`

`

`2668
`
`HOMAGNE at all
`
`BLOOD. 24 SEPTEMBER 2009 - VOLUME 114. NUMBER 13
`
`class I specificitics. Netct’llteless. all people appear to also harbor
`stiltlt.‘ NK cells that are inhibited by only one Ml-{t‘ class i
`allotypc.'-‘-' ‘ Thus. the NK population as a \\ hole may detect loss ol'
`even a single ”LA class I allotype. allot-ting killing of target cells
`dclicienl
`itt only one or a
`less class i allotypes." The clinical
`relevance ol' such tttissittg—scll‘ recognition has hectt demonstrated
`in patients with acute tttycloid leukemia tt\Ml.i. it] which haploitlctt—
`Iical stem cell transplantation IS{'T} led to cspansiott attd activa—
`liott ot' dimot-derived. K|[(—ll|.r\ class l-tttisntalchcd NKeeils.
`
`resulting in NK cell -ntediated anlilcukemia responses associated
`with rcduccd risk of relapse and increased survival rates. with no
`risk ol' gral't-versus—host discase.‘ ‘ ‘7 llowerer.
`l'cw patients with
`AM[. are candidates l'ot' tt‘:tnsplant»hascd therapy. and thus. novel
`tt‘ealtt‘tclit options are urgently needed. To explore the feasibility of
`acltiet ing similar NK-mediated anlileukcmia activity by a pharma—
`cologic approach that would circumvent
`the need l'or S("|'. Wt:
`gcnctated l'ttlly hutttatt anti-KIR monoclonal antihodics tombs}
`that block the interactions ol‘ the 3 main inhibitory Kll'{2|)l. with
`their l-lt..v\—(‘ ligands. thereby enhancing NK activity. In this study.
`we present tile in vitro and iii \‘ivo chat'actcrizalion ol' l—7F‘J. which
`l'ot'tncd the basis lin' selection of tltis tttAh as candidate for clinical
`
`development.
`
`
`Methods
`
`Cell isolation
`
`.-\ll patient samples were collected and stored under institutional review
`hoard approved protocols.
`l’atients piosided pttot' written informed con.
`sent iIt accordata'c with the Declaration oi | Ielsittki. approved hy the Ohio
`State tfniterstty {'otttprcltensit'e ('ancer ('cntet' Institutional Review liottt‘d
`I'or use oi samples. AMI, blasts were isolated trout bone marrow aspirate at
`diagnosis and cry:iprescr't'ed. Sample viability was more than that. Patients
`received induction and consolidation clu-tttothci'iltty- and upon cottlltlete
`remission. peripheral lilood tuotionoclcat cells tl’ilM('t were obtained hy
`l'icoll—Ilypaqttc density gradient centl'ilttgatiott. which were the source ol'
`:ttttologous NK cells [or t'onctional assays with paticnt-derit-cd target cells.
`l-or sortie experiments. Nts’ cells than these patiettt samples. or
`iron]
`healthy donors till .i\ class I high resolution typed}. were depicted oil cells
`hy Itegattte {1}} imunmontagnettc selection tMiltenyi iiiolccr sltmttlatctl
`with irradiated Pita-IF I'ceder cells. phytoltcmaggltttinin tBiochromt. and
`fitltl liinil . Interleukin tll.t 2 tt'hiront. and espandcd list up to 2 months.”
`Purity of NK cells was coutirmed by How cytometry. and was at least 352$
`C‘llfio ' ('lJ.l
`Iyntpltia-ytes itt all L'\pel'iltlellls. NK-ccll clones were gCIlL'I"
`aled i'I'om Pit-MC ul'healthy donors."r
`
`IgtIiI. and
`rclones lilio.
`spectlic l'oi- KlRllllJi’Sl
`Murine tttAhs
`XAi-li. lng. KIREINJ. {“53 l[clones ULIH}. lgfil. and Y34U. Ith.
`K|R2|)|.l. Q. -.iiSI. S]. ‘55 [clone |)F2tltl.
`IgUIl. KlRZDS-l {clone
`fit-SH]. ngilai. HIA class I tclotte Act—130. lng. and NKGEA {clone
`Kl‘t‘l.
`lgtilht have been described?“ l‘hycoerytltt‘in tl’lit conjugated
`attti-KIR atttihodics were l'rotn lieckman ('oultct'.
`l-luman lg(i4 tITJKS;
`Signal-Aldrich] was used as control for I—Tl-‘ii.
`
`Flow cylometry
`
`('el’iiittes. A total at ltl‘ cells was incubated at -l"(‘ with l ugfntl.. pui'itied
`human t l-i'l-‘UJ or muriue tl'illti. (il.ltt_l. attdi’ot' HES] i2} anti-KlR tl‘lr\hh.
`I'ollowcd hy I’ll-conjugated ntouse anti—human lgti-l till'otlZS: Southern
`
`ltiotcchnolot. - Associates: or l’l€-t'iitt_|'ttgtttt‘tl goat anti—mouse lgG IBeck-
`tttatt (‘ooltcrt Percentages ol'aoti—KIRJI) binding were calculated using the
`I'ollowittg l'ormuia: percentage of binding " MFI
`tmeao tluorescencc
`
`intensityt ('JMFI (_'
`:4” Hill. where (I. is tltc anti—KIREI) concentration in
`micrograms per tniililitertl agimln'cpt'L-sents Itltlfl't-i.
`NK populations.
`'l‘hrec-color intntuttothtot'eseettce was used to atta-
`lyre expression of KIR and NKGEA on CIJFto' NK cells. NK cells were
`ittcttliated with alIophycocyattin-coitiugated anti—('DSo tlgGl t plus uncon-
`_iugalcd anti—NKUZA tlgGZh}.
`t‘ollowed by ltuorescein isothiocyanate—
`conjugated goat anti-mouse lg(12h antihodies tSoutltern Biotechnology
`Associatesi. in comhination with l’l-i-eott'tugalcd anti-K |R3])l SIMS: telonc
`til.lts'3. |g(i I I. anti-KlRleLli'Sl tclotte liBtdS. lgfj l t. oraoti—KIIUIMJISI
`tclotte KIT. lgt‘l'il I.
`H'itrtit' Maori staining.
`Blood samples were incubated at
`Ietitperalttre with PH—cottittgated l-TF‘J and eon‘tl‘tiltaliol‘is of cell
`specilic mobs. as indicated.
`Binding assays. Fusion proteins consisting ol‘ tlte extracellular part of
`Kll<2l)l..l attached to he part of marine or ltttittait
`IgGl
`[designated
`KiRllllJ-ml‘c attd -hl"c. respectively: were incubated with human t l-7l-"lt
`or mouse [I'Jlt'lllll or (iLlHfil
`(lltlt-KIR ntAhs I'ot'
`.‘ill‘ttilttlles on ice.
`I.('l.?2l.22|-('w-t cells were added and incubated tor
`lltour on ice.
`
`room
`type—
`
`washed. attd incubated with aIlophycocyaniii—conjugated littth’l; goat
`anti human lgti or anti—mouse lgG. and analyzed by Ilow cytometry.
`('iJifJFIIi-W—y its-say. Cells were processed. as described?“ lirielly.
`NK cells or I‘B MC were incubated for 4 hours at .t?‘-'(‘ in the presence of 5 MM
`Inonensin [Sigllltldflldl‘iuhl and fluorescent
`istitltiocyanale-utnjugated anti-
`(‘l)ltl'i'a and —h tnAhs. witlt or without anti-KIR mAbs. and with or without
`target cells. Alter incubation, cells were washed in phosphate—hittiered
`saline and 3 tttM liUl'A tethylenediaminelclraaeelic acid] and stained I'ol'
`extracellular market