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

Mixed lineage leukemia (MLL) (KMT2A) rearrangements (KMT2Ar) 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 MLL translocation and half of t...

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Autores principales: Secker, Kathy-Ann, Bruns, Lukas, Keppeler, Hildegard, Jeong, Johan, Hentrich, Thomas, Schulze-Hentrich, Julia M., Mankel, Barbara, Fend, Falko, Schneidawind, Dominik, Schneidawind, Corina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352867/
https://www.ncbi.nlm.nih.gov/pubmed/32517300
http://dx.doi.org/10.3390/cancers12061487
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author Secker, Kathy-Ann
Bruns, Lukas
Keppeler, Hildegard
Jeong, Johan
Hentrich, Thomas
Schulze-Hentrich, Julia M.
Mankel, Barbara
Fend, Falko
Schneidawind, Dominik
Schneidawind, Corina
author_facet Secker, Kathy-Ann
Bruns, Lukas
Keppeler, Hildegard
Jeong, Johan
Hentrich, Thomas
Schulze-Hentrich, Julia M.
Mankel, Barbara
Fend, Falko
Schneidawind, Dominik
Schneidawind, Corina
author_sort Secker, Kathy-Ann
collection PubMed
description Mixed lineage leukemia (MLL) (KMT2A) rearrangements (KMT2Ar) 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 MLL translocation and half of them are t(4;11), resulting in a poor prognosis. In contrast, in adults only 10% of acute myeloid leukemia (AML) bear t(9;11) with an intermediate prognosis. The reasons for these differences are poorly understood. Recently, we established an efficient CRISPR/Cas9-based KMT2Ar 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 KMT2Ar cells showed monoclonal outgrowth with an immature morphology, myelomonocytic phenotype and elevated KMT2Ar target gene expression comparable to patient cells. Strikingly, all KMT2Ar cells presented with indefinite growth potential except for MLL-AF4 huBM cells ceasing proliferation after 80 days. We uncovered FFAR2, an epigenetic tumor suppressor, as potentially responsible for the inability of MLL-AF4 to immortalize adult cells under myeloid conditions.
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spelling pubmed-73528672020-07-15 Only Hematopoietic Stem and Progenitor Cells from Cord Blood Are Susceptible to Malignant Transformation by MLL-AF4 Translocations Secker, Kathy-Ann Bruns, Lukas Keppeler, Hildegard Jeong, Johan Hentrich, Thomas Schulze-Hentrich, Julia M. Mankel, Barbara Fend, Falko Schneidawind, Dominik Schneidawind, Corina Cancers (Basel) Article Mixed lineage leukemia (MLL) (KMT2A) rearrangements (KMT2Ar) 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 MLL translocation and half of them are t(4;11), resulting in a poor prognosis. In contrast, in adults only 10% of acute myeloid leukemia (AML) bear t(9;11) with an intermediate prognosis. The reasons for these differences are poorly understood. Recently, we established an efficient CRISPR/Cas9-based KMT2Ar 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 KMT2Ar cells showed monoclonal outgrowth with an immature morphology, myelomonocytic phenotype and elevated KMT2Ar target gene expression comparable to patient cells. Strikingly, all KMT2Ar cells presented with indefinite growth potential except for MLL-AF4 huBM cells ceasing proliferation after 80 days. We uncovered FFAR2, an epigenetic tumor suppressor, as potentially responsible for the inability of MLL-AF4 to immortalize adult cells under myeloid conditions. MDPI 2020-06-07 /pmc/articles/PMC7352867/ /pubmed/32517300 http://dx.doi.org/10.3390/cancers12061487 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Secker, Kathy-Ann
Bruns, Lukas
Keppeler, Hildegard
Jeong, Johan
Hentrich, Thomas
Schulze-Hentrich, Julia M.
Mankel, Barbara
Fend, Falko
Schneidawind, Dominik
Schneidawind, Corina
Only Hematopoietic Stem and Progenitor Cells from Cord Blood Are Susceptible to Malignant Transformation by MLL-AF4 Translocations
title Only Hematopoietic Stem and Progenitor Cells from Cord Blood Are Susceptible to Malignant Transformation by MLL-AF4 Translocations
title_full Only Hematopoietic Stem and Progenitor Cells from Cord Blood Are Susceptible to Malignant Transformation by MLL-AF4 Translocations
title_fullStr Only Hematopoietic Stem and Progenitor Cells from Cord Blood Are Susceptible to Malignant Transformation by MLL-AF4 Translocations
title_full_unstemmed Only Hematopoietic Stem and Progenitor Cells from Cord Blood Are Susceptible to Malignant Transformation by MLL-AF4 Translocations
title_short Only Hematopoietic Stem and Progenitor Cells from Cord Blood Are Susceptible to Malignant Transformation by MLL-AF4 Translocations
title_sort only hematopoietic stem and progenitor cells from cord blood are susceptible to malignant transformation by mll-af4 translocations
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352867/
https://www.ncbi.nlm.nih.gov/pubmed/32517300
http://dx.doi.org/10.3390/cancers12061487
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