title: Conditional Expression of E2A-HLF Induces B-Cell Precursor Death and Myeloproliferative-Like Disease in Knock-In Mice.
abstract: Chromosomal translocations are driver mutations of human cancers, particularly leukemias. They define disease subtypes and are used as prognostic markers, for minimal residual disease monitoring and therapeutic targets. Due to their low incidence, several translocations and their biological consequences remain poorly characterized. To address this, we engineered mouse strains that conditionally express E2A-HLF, a fusion oncogene from the translocation t(17;19) associated with 1% of pediatric B-cell precursor ALL. Conditional oncogene activation and expression were directed to the B-cell compartment by the Cre driver promoters CD19 or Mb1 (Igα, CD79a), or to the hematopoietic stem cell compartment by the Mx1 promoter. E2A-HLF expression in B-cell progenitors induced hyposplenia and lymphopenia, whereas expression in hematopoietic stem/progenitor cells was embryonic lethal. Increased cell death was detected in E2A-HLF expressing cells, suggesting the need for cooperating genetic events that suppress cell death for B-cell oncogenic transformation. E2A-HLF/Mb1.Cre aged mice developed a fatal myeloproliferative-like disorder with low frequency characterized by leukocytosis, anemia, hepatosplenomegaly and organ-infiltration by mature myelocytes. In conclusion, we have developed conditional E2A-HLF knock-in mice, which provide an experimental platform to study cooperating genetic events and further elucidate translational biology in cross-species comparative studies.
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Jesús
authors.initials: J
authors.lastname: Duque-Afonso
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Smith
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Cleary
mesh_terms: D000818:Animals; D018941:Antigens, CD19 / Q000235:genetics / Q000378:metabolism; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics* / Q000378:metabolism; D051925:CD79 Antigens / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D015870:Gene Expression; D055879:Gene Knock-In Techniques; D005818:Genetic Engineering; D006529:Hepatomegaly / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D064547:Myxovirus Resistance Proteins / Q000235:genetics / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D054448:Precursor Cells, B-Lymphoid / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic; D013163:Splenomegaly / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014178:Translocation, Genetic
chemical_list: D018941:Antigens, CD19; D050976:Basic-Leucine Zipper Transcription Factors; D051925:CD79 Antigens; C489626:E2a-Hlf fusion protein, mouse; C579070:Mx1 protein, mouse; D064547:Myxovirus Resistance Proteins; D015514:Oncogene Proteins, Fusion; C045073:Cre recombinase; D019426:Integrases