title: Ikaros deficiency in host hematopoietic cells separates GVL from GVHD after experimental allogeneic hematopoietic cell transplantation.
abstract: The graft-versus-leukemia (GVL) effect following allogeneic hematopoietic stem cell transplantation (allo-HCT) is critical for its curative potential. Hwever, GVL is tightly linked to graft-versus-host disease (GVHD). Among hematological malignancies, acute lymphoblastic leukemia (ALL) is the most resistant to GVL, although the reasons for this remain poorly understood. Clinical studies have identified alterations in Ikaros (Ik) transcription factor as the major marker associated with poor outcomes in ALL. We have shown that the absence of Ik in professional host-derived hematopoietic antigen-presenting cells (APCs) exacerbates GVHD. However, whetherIkexpression plays a role in resistance to GVL is not known. In this study we used multiple clinically relevant murine models of allo-HCT to explore whetherIkexpression in hematopoietic APCs and/or leukemic cells is critical for increasing resistance to GVL and thus inducing relapse. We found thatIkdeficiency in host APCs failed to enhance GVL despite increased GVHD severity. Mechanistic studies with bone marrow (BM) chimeras and tetramer analyses demonstrated reduced tumor-specific immunodominant (gag+) antigen responses in the [B6Ik-/-→B6] group. Loss of GVL was observed when both the leukemia cells and the host APCs were deficient inIk. We found that calreticulin (CRT) expression in host antigen-presenting dendritic cells (DCs) ofIk-/-animals was significantly lower than in wild-type animals. Rescuing CRT expression inIk-/-DCs improved leukemic-specific cytotoxic T cell function. Together, our data demonstrate that the absence of Ikaros in host hematopoietic cells promotes resistance to GVL despite increasing GVHD and thus provides a potential mechanism for the poor outcome ofIk-/-ALL patients.
authors.affiliation: Department of Internal Medicine; University of Michigan Comprehensive Cancer Center ; Ann Arbor, MI USA.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Toubai
authors.affiliation: Department of Pediatrics and Communicable Diseases; University of Michigan Medical School ; Ann Arbor, MI USA.
authors.forename: Hou
authors.initials: H
authors.lastname: Guoqing
authors.affiliation: Department of Internal Medicine; University of Michigan Comprehensive Cancer Center ; Ann Arbor, MI USA.
authors.forename: Corrine
authors.initials: C
authors.lastname: Rossi
authors.affiliation: Department of Internal Medicine; University of Michigan Comprehensive Cancer Center ; Ann Arbor, MI USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Mathewson
authors.affiliation: Department of Internal Medicine; University of Michigan Comprehensive Cancer Center ; Ann Arbor, MI USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Oravecz-Wilson
authors.affiliation: Department of Internal Medicine; University of Michigan Comprehensive Cancer Center ; Ann Arbor, MI USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Cummings
authors.affiliation: Department of Internal Medicine; University of Michigan Comprehensive Cancer Center ; Ann Arbor, MI USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Internal Medicine; University of Michigan Comprehensive Cancer Center ; Ann Arbor, MI USA.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Pediatrics and Communicable Diseases; University of Michigan Medical School ; Ann Arbor, MI USA.
authors.forename: Sung
authors.initials: S
authors.lastname: Choi
authors.affiliation: Department of Internal Medicine; University of Michigan Comprehensive Cancer Center ; Ann Arbor, MI USA.
authors.forename: Pavan
authors.initials: P
authors.lastname: Reddy
keywords: 51Cr, Chromium-51; ALL, acute lymphoblastic leukemia; APC, allophycocyanin; APCs, antigen-presenting cells; Allo-HCT, allogeneic hematopoietic stem cell transplantation; BC, blast crisis; BLI, bioluminescence imaging; BM, bone marrow; BMDCs, bone marrow derived dendritic cells; BMT, bone marrow transplantation; CML, chronic myeloid leukemia; CRT, calreticulin; CTL, cytotoxic T cell; DCs, dendritic cells; FACS, Fluorescence-activated cell sorting; FBS, fatal bovine serum; FITC, fluorescein isothiocyanate; GVHD, graft-versus-host-disease; GVL, graft-versus-leukemia; HCT, hematopoietic stem cell transplantation; ICAM-1, intracellular adhesion molecule 1; Ik DN, Ikaros dominant negative; Ik, Ikaros; Ikaros; MACS, magnetic- activated cell sorting; MBL-2, moloney-murine sarcoma virus-induced MBL-2 lymphoma cells; MHC, major histocompatibility complex; MLR, mixed lymphocyte reaction; MiHAs, multiple minor histocompatibility antigens; PBS, phosphate buffered saline; PE, phycoerythrin; SIRP-α, signal regulatory protein α; TCD-BM, T cell depleted bone marrow; TSA, tumor specific antigen; Tregs, regulatory T cells; UCUCA, University Committee on Use and Care of Animals; WT, wild-type; antigen-presenting cells; bone marrow transplantation; graft-versus-leukemia; luc+, luciferase+; mAbs, monoclonal antibodies; mCRT, murine calreticulin