The immune checkpoint ICOSLG is a relapse-predicting biomarker and therapeutic target in infant t(4;11) acute lymphoblastic leukemia
Marius Külp,
Anna Lena Siemund,
Patrizia Larghero,
Alissa Dietz,
Julia Alten,
Gunnar Cario,
Cornelia Eckert,
Aurélie Caye-Eude,
Hélène Cavé,
Michela Bardini,
Giovanni Cazzaniga,
Paola De Lorenzo,
Maria Grazia Valsecchi,
Laura Diehl,
Halvard Bonig,
Claus Meyer,
Rolf Marschalek
Affiliations
Marius Külp
Diagnostic Center of Acute Leukemia (DCAL), Institute of Pharmaceutical Biology, Goethe-University, University of Frankfurt, Max-von-Laue-Str. 9, Frankfurt am Main, Germany
Anna Lena Siemund
Diagnostic Center of Acute Leukemia (DCAL), Institute of Pharmaceutical Biology, Goethe-University, University of Frankfurt, Max-von-Laue-Str. 9, Frankfurt am Main, Germany
Patrizia Larghero
Diagnostic Center of Acute Leukemia (DCAL), Institute of Pharmaceutical Biology, Goethe-University, University of Frankfurt, Max-von-Laue-Str. 9, Frankfurt am Main, Germany
Alissa Dietz
Diagnostic Center of Acute Leukemia (DCAL), Institute of Pharmaceutical Biology, Goethe-University, University of Frankfurt, Max-von-Laue-Str. 9, Frankfurt am Main, Germany
Julia Alten
Department of Pediatrics, University Medical Center Schleswig-Holstein, Campus Kiel, Germany
Gunnar Cario
Department of Pediatrics, University Medical Center Schleswig-Holstein, Campus Kiel, Germany
Cornelia Eckert
Department of Pediatric Hematology and Oncology, Charité-Universitätsmedizin Berlin, Berlin, Germany
Aurélie Caye-Eude
Département de Génétique, Hôpital Robert Debré, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris, France
Hélène Cavé
Département de Génétique, Hôpital Robert Debré, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris, France
Michela Bardini
Centro Ricerca Tettamanti, Pediatrics, University of Milan-Bicocca, Fondazione Monza e Brianza per il Bambino e la sua Mamma (MBBM)/San Gerardo Hospital, Monza, Italy
Giovanni Cazzaniga
Centro Ricerca Tettamanti, Pediatrics, University of Milan-Bicocca, Fondazione Monza e Brianza per il Bambino e la sua Mamma (MBBM)/San Gerardo Hospital, Monza, Italy; Genetics, School of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy
Paola De Lorenzo
Statistical Section, Pediatric Clinic, University of Milano-Bicocca, Monza, Italy
Maria Grazia Valsecchi
Center of Bioinformatics, Biostatistics and Bioimaging, University of Milano-Bicocca, Monza, Italy
Laura Diehl
Institute for Transfusion Medicine and Immunohematology, Goethe University, Frankfurt am Main, Germany; German Red Cross Blood Service Baden-Württemberg-Hessen, Frankfurt am Main, Germany
Halvard Bonig
Institute for Transfusion Medicine and Immunohematology, Goethe University, Frankfurt am Main, Germany; German Red Cross Blood Service Baden-Württemberg-Hessen, Frankfurt am Main, Germany; Department of Medicine, Division of Hematology, University of Washington School of Medicine, Seattle, WA, USA
Claus Meyer
Diagnostic Center of Acute Leukemia (DCAL), Institute of Pharmaceutical Biology, Goethe-University, University of Frankfurt, Max-von-Laue-Str. 9, Frankfurt am Main, Germany
Rolf Marschalek
Diagnostic Center of Acute Leukemia (DCAL), Institute of Pharmaceutical Biology, Goethe-University, University of Frankfurt, Max-von-Laue-Str. 9, Frankfurt am Main, Germany; Corresponding author
Summary: The most frequent genetic aberration leading to infant ALL (iALL) is the chromosomal translocation t(4;11), generating the fusion oncogenes KMT2A:AFF1 and AFF1:KMT2A, respectively. KMT2A-r iALL displays a dismal prognosis through high relapse rates and relapse-associated mortality. Relapse occurs frequently despite ongoing chemotherapy and without the accumulation of secondary mutations. A rational explanation for the observed chemo-resistance and satisfactory treatment options remain to be elucidated. We found that elevated ICOSLG expression level at diagnosis was associated with inferior event free survival (EFS) in a cohort of 43 patients with t(4;-11) iALL and that a cohort of 18 patients with iALL at relapse displayed strongly increased ICOSLG expression. Furthermore, co-culturing t(4;11) ALL cells (ICOSLGhi) with primary T-cells resulted in the development of Tregs. This was impaired through treatment with a neutralizing ICOSLG antibody. These findings imply ICOSLG (1) as a relapse-predicting biomarker, and (2) as a therapeutic target involved in a potential immune evasion relapse-mechanism of infant t(4;11) ALL.
