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.

Critical Modulation of Hematopoietic Lineage Fate by Hepatic Leukemia Factor

“…However, as we have failed to observe leukemia upon Hlf induction, even following extensive time periods, additional mechanisms other than aberrant activation of Hlf target genes seem crucial for E2A-HLF-mediated transformation. At the same time, our studies appear in line with the observed phenotypes of murine transgenic models of the E2A-HLF fusion that manifest with myelo- rather than lymphoproliferation ( Duque-Afonso et al., 2015 ).…”

Acute lymphoblastic leukemia with the t(17;19) translocation: hope has appeared! Multimodal immunotherapy in a 3-year-old child with refractory disease: a case report

“…The t (17;19) Ранее на различных животных моделях было показано, что транслокации t(17;19) как единственного генетического события недостаточно для развития ОЛЛ [18,19]. В одном из исследований было показано, что экспрессия TCF3-HLF в гемопоэтических стволовых клетках приводит к летальному исходу на уровне эмбриона, в то время как экспрессия на уровне предшественников В-лим-…”

Eya2 is critical for the E2A‑HLF‑mediated immortalization of mouse hematopoietic stem/progenitor cells

“…In addition, the conditional expression of E2A-HLF prevents apoptosis induced by cytokine withdrawal in interleukin (IL)-3-dependent mouse Ba/F3 cells (13). However, B-cell progenitor-specific conditional E2A-HLF knock-in mice exhibit hyposplenia and lymphopenia, whereas hematopoietic stem/progenitor cell (HSPC)-specific ones are embryonically lethal (14). The E2A-HLF fusion likely requires additional events to cause leukemia, since immunoglobulin enhancer and promoter-driven E2A-HLF transgenic and knock-in mice exhibit maturation arrest and apoptosis in cells expressing E2A-HLF (14)(15)(16).…”

“…However, B-cell progenitor-specific conditional E2A-HLF knock-in mice exhibit hyposplenia and lymphopenia, whereas hematopoietic stem/progenitor cell (HSPC)-specific ones are embryonically lethal (14). The E2A-HLF fusion likely requires additional events to cause leukemia, since immunoglobulin enhancer and promoter-driven E2A-HLF transgenic and knock-in mice exhibit maturation arrest and apoptosis in cells expressing E2A-HLF (14)(15)(16). Numerous molecules downstream of E2A-HLF or cooperative with E2A-HLF have since been identified, including transcription factor Lim domain only 2 (LMO2), which is involved in T-cell ALL (17,18); snail family transcriptional repressor 2 (19); nuclear factor, interleukin 3 regulated (20); Groucho-related genes (21); Annexin VIII and sushi-repeat protein upregulated in leukemia, which have paraneoplastic roles in E2A-HLF-expressing leukemia (22); Zfp521 (23); survivin (24); and death receptors DR4/DR5 (25).…”