Enforced expression of MLL-AF4 fusion in cord blood CD34+ cells enhances the hematopoietic repopulating cell function and clonogenic potential but is not sufficient to initiate leukemia

• Published in: Blood 2011-05, Vol.117 (18), p.4746-4758
• Main Authors: Montes, Rosa, Ayllón, Verónica, Gutierrez-Aranda, Ivan, Prat, Isidro, Hernández-Lamas, M. Carmen, Ponce, Laura, Bresolin, Silvia, te Kronnie, Geertruy, Greaves, Mel, Bueno, Clara, Menendez, Pablo
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Base Sequence; Biological and medical sciences; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Chromosome aberrations; DNA Primers - genetics; Fetal Blood - cytology; Fetal Blood - metabolism; Gene Expression; Hematologic and hematopoietic diseases; Hematopoietic Stem Cells - metabolism; Hematopoietic Stem Cells - pathology; Humans; Infant; Infant, Newborn; Interleukin Receptor Common gamma Subunit - deficiency; Interleukin Receptor Common gamma Subunit - genetics; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical genetics; Medical sciences; Mice; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Myeloid-Lymphoid Leukemia Protein - genetics; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Oncogene Proteins, Fusion - genetics; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - etiology; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - pathology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2010-12-322230

Infant acute lymphoblastic leukemia harboring the fusion mixed-lineage leukemia (MLL)-AF4 is associated with a dismal prognosis and very brief latency. Our limited understanding of transformation by MLL-AF4 is reflected in murine models, which do not accurately recapitulate the human disease. Human models for MLL-AF4 disease do not exist. Hematopoietic stem or progenitor cells (HSPCs) represent probable targets for transformation. Here, we explored in vitro and in vivo the impact of the enforced expression of MLL-AF4 in human cord blood-derived CD34+ HSPCs. Intrabone marrow transplantation into NOD/SCID-IL2Rγ−/− mice revealed an enhanced multilineage hematopoietic engraftment, efficiency, and homing to other hematopoietic sites on enforced expression of MLL-AF4. Lentiviral transduction of MLL-AF4 into CD34+ HSPCs increased the in vitro clonogenic potential of CD34+ progenitors and promoted their proliferation. Consequently, cell cycle and apoptosis analyses suggest that MLL-AF4 conveys a selective proliferation coupled to a survival advantage, which correlates with changes in the expression of genes involved in apoptosis, sensing DNA damage and DNA repair. However, MLL-AF4 expression was insufficient to initiate leukemogenesis on its own, indicating that either additional hits (or reciprocal AF4-MLL product) may be required to initiate ALL or that cord blood-derived CD34+ HSPCs are not the appropriate cellular target for MLL-AF4-mediated ALL.