title: MPL expression on AML blasts predicts peripheral blood neutropenia and thrombocytopenia.
abstract: Although the molecular pathways that cause acute myeloid leukemia (AML) are increasingly well understood, the pathogenesis of peripheral blood cytopenia, a major cause of AML mortality, remains obscure. A prevailing assumption states that AML spatially displaces nonleukemic hematopoiesis from the bone marrow. However, examining an initial cohort of 223 AML patients, we found no correlation between bone marrow blast content and cytopenia, questioning the displacement theory. Measuring serum concentration of thrombopoietin (TPO), a key regulator of hematopoietic stem cells and megakaryocytes, revealed loss of physiologic negative correlation with platelet count in AML cases with blasts expressing MPL, the thrombopoietin (scavenging) receptor. Mechanistic studies demonstrated that MPLhiblasts could indeed clear TPO, likely therefore leading to insufficient cytokine levels for nonleukemic hematopoiesis. Microarray analysis in an independent multicenter study cohort of 437 AML cases validated MPL expression as a central predictor of thrombocytopenia and neutropenia in AML. Moreover, t(8;21) AML cases demonstrated the highest average MPL expression and lowest average platelet and absolute neutrophil counts among subgroups. Our work thus explains the pathophysiology of peripheral blood cytopenia in a relevant number of AML cases.
authors: Hematology, University Hospital and University of Zurich, Zurich, Switzerland.|Department of Medicine, Boston University School of Medicine, Boston, MA.
authors: Philipp J
authors: PJ
authors: Rauch
authors: Hematology, University Hospital and University of Zurich, Zurich, Switzerland.
authors: Jana M
authors: JM
authors: Ellegast
authors: Hematology, University Hospital and University of Zurich, Zurich, Switzerland.
authors: Corinne C
authors: CC
authors: Widmer
authors: Hematology, University Hospital and University of Zurich, Zurich, Switzerland.
authors: Kristin
authors: K
authors: Fritsch
authors: Hematology, University Hospital and University of Zurich, Zurich, Switzerland.
authors: Jeroen S
authors: JS
authors: Goede
authors: Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands; and.
authors: Peter J M
authors: PJ
authors: Valk
authors: Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands; and.
authors: Bob
authors: B
authors: Löwenberg
authors: Hematology, University Hospital and University of Zurich, Zurich, Switzerland.|International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors: Hitoshi
authors: H
authors: Takizawa
authors: Hematology, University Hospital and University of Zurich, Zurich, Switzerland.
authors: Markus G
authors: MG
authors: Manz
mesh_terms: D015331:Cohort Studies; D055879:Gene Knock-In Techniques; D006410:Hematopoiesis / Q000502:physiology; D064593:Heterografts; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D009503:Neutropenia / Q000209:etiology / Q000503:physiopathology*; D053628:Receptors, Thrombopoietin / Q000096:biosynthesis*; D013921:Thrombocytopenia / Q000209:etiology / Q000503:physiopathology*; D013926:Thrombopoietin / Q000097:blood; D059467:Transcriptome
chemical_list: D053628:Receptors, Thrombopoietin; C082218:MPL protein, human; D013926:Thrombopoietin