Only Hematopoietic Stem and Progenitor Cells from Cord Blood Are Susceptible to Malignant Transformation by <i>MLL-AF4</i> Translocations

• Main Authors: Kathy-Ann Secker, Lukas Bruns, Hildegard Keppeler, Johan Jeong, Thomas Hentrich, Julia M. Schulze-Hentrich, Barbara Mankel, Falko Fend, Dominik Schneidawind, Corina Schneidawind
• Format: Article
• Language: English
• Published: MDPI AG 2020-06-01
• Series: Cancers
• Subjects: <i>KMT2A</i>-rearranged leukemia; CRISPR/Cas9; cell of origin
• Online Access: https://www.mdpi.com/2072-6694/12/6/1487

<i>Mixed lineage leukemia</i> (<i>MLL</i>) <i>(KMT2A)</i> rearrangements (<i>KMT2A</i>r) play a crucial role in leukemogenesis. Dependent on age, major differences exist regarding disease frequency, main fusion partners and prognosis. In infants, up to 80% of acute lymphoid leukemia (ALL) bear a <i>MLL</i> translocation and half of them are <i>t</i>(4;11), resulting in a poor prognosis. In contrast, in adults only 10% of acute myeloid leukemia (AML) bear <i>t</i>(9;11) with an intermediate prognosis. The reasons for these differences are poorly understood. Recently, we established an efficient CRISPR/Cas9-based <i>KMT2A</i>r model in hematopoietic stem and progenitor cells (HSPCs) derived from human cord blood (huCB) and faithfully mimicked the underlying biology of the disease. Here, we applied this model to HSPCs from adult bone marrow (huBM) to investigate the impact of the cell of origin and fusion partner on disease development. Both genome-edited infant and adult <i>KMT2A</i>r cells showed monoclonal outgrowth with an immature morphology, myelomonocytic phenotype and elevated <i>KMT2A</i>r target gene expression comparable to patient cells. Strikingly, all <i>KMT2A</i>r cells presented with indefinite growth potential except for <i>MLL-AF4</i> huBM cells ceasing proliferation after 80 days. We uncovered <i>FFAR2</i>, an epigenetic tumor suppressor, as potentially responsible for the inability of <i>MLL-AF4</i> to immortalize adult cells under myeloid conditions.