title: Clonal conversion of B lymphoid leukemia reveals cross-lineage transfer of malignant states.
abstract: Even though leukemia is considered to be confined to one specific hematopoietic cell type, cases of acute leukemia of ambiguous lineage and patients relapsing in phenotypically altered disease suggest that a malignant state may be transferred between lineages. Because B-cell leukemia is associated with mutations in transcription factors of importance for stable preservation of lineage identity, we here investigated the potential lineage plasticity of leukemic cells. We report that primary pro-B leukemia cells from mice carrying heterozygous mutations in either or both the Pax5 and Ebf1 genes, commonly mutated in human leukemia, can be converted into T lineage leukemia cells. Even though the conversion process involved global changes in gene expression and lineage-restricted epigenetic reconfiguration, the malignant phenotype of the cells was preserved, enabling them to expand as T lineage leukemia cells in vivo. Furthermore, while the transformed pro-B cells displayed plasticity toward myeloid lineages, the converted cells failed to cause myeloid leukemia after transplantation. These data provide evidence that a malignant phenotype can be transferred between hematopoietic lineages. This has important implications for modern cancer medicine because lineage targeted treatment of leukemia patients can be predicted to provoke the emergence of phenotypically altered subclones, causing clinical relapse.
authors.affiliation: Department of Clinical and Experimental Medicine, Experimental Hematopoiesis Unit, Faculty of Health Sciences, Linköping University, 58183 Linkoping, Sweden.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Somasundaram
authors.affiliation: Department of Clinical and Experimental Medicine, Experimental Hematopoiesis Unit, Faculty of Health Sciences, Linköping University, 58183 Linkoping, Sweden.
authors.forename: Josefine
authors.initials: J
authors.lastname: Åhsberg
authors.affiliation: Department of Clinical and Experimental Medicine, Experimental Hematopoiesis Unit, Faculty of Health Sciences, Linköping University, 58183 Linkoping, Sweden.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Okuyama
authors.affiliation: Department of Clinical and Experimental Medicine, Experimental Hematopoiesis Unit, Faculty of Health Sciences, Linköping University, 58183 Linkoping, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Ungerbäck
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Genetics, Lund University, 22184 Lund, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Lilljebjörn
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Genetics, Lund University, 22184 Lund, Sweden.
authors.forename: Thoas
authors.initials: T
authors.lastname: Fioretos
authors.affiliation: Department of Clinical and Experimental Medicine, Experimental Hematopoiesis Unit, Faculty of Health Sciences, Linköping University, 58183 Linkoping, Sweden.
authors.forename: Tobias
authors.initials: T
authors.lastname: Strid
authors.affiliation: Department of Clinical and Experimental Medicine, Experimental Hematopoiesis Unit, Faculty of Health Sciences, Linköping University, 58183 Linkoping, Sweden.|Division of Molecular Hematology Lund University, 22184 Lund, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Sigvardsson
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000473:pathology*; D002460:Cell Line; D045744:Cell Line, Tumor; D019070:Cell Lineage; D049109:Cell Proliferation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007945:Leukemia, Lymphoid / Q000503:physiopathology*; D015458:Leukemia, T-Cell / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D022423:Myeloid Cells / Q000473:pathology; D054448:Precursor Cells, B-Lymphoid / Q000378:metabolism; D011485:Protein Binding; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D051880:Receptors, Notch
keywords: B-ALL; lineage conversion; transcription factors