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.
Highlights
Acute lymphoblastic leukemia (ALL) is a heterogenous disease comprised of several genetic subtypes, which are defined by genomic alterations including chromosomal aberrations, copy number variations and somatic mutations [1]
Expression of the conditional E2A-HLF allele was achieved in B cell progenitors using Cre recombinase under the control of B-cell specific promoters CD19 or Mb1 (Igα, CD79a) or in hematopoietic stem/progenitor cells using the Mx1 promoter (Fig 1A)
In E2A-HLF/Mb1-Cre mice, GFP expression was detected in ~20% of mature B cells (CD19+B220+) and 85% of B cell progenitors (LinCD19+CD43+) compared to fewer than 1% of mature myeloid Mac1+ cells and T cell subsets of peripheral blood
Summary
Acute lymphoblastic leukemia (ALL) is a heterogenous disease comprised of several genetic subtypes, which are defined by genomic alterations including chromosomal aberrations, copy number variations and somatic mutations [1]. Genomic alterations confer the malignant clone different functional properties and are associated with prognosis, treatment response and relapse [2]. Recurring chromosomal translocations were the first genetic alterations characterized at the molecular level and in transgenic mice, and are associated with disease initiation and progression of hematological malignancies [3,4]. ALL is the most common childhood cancer [5], several chromosomal translocations defining ALL subtypes remain poorly characterized due to their low frequency.
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