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

Cancers
Kathy-Ann SeckerCorina Schneidawind

Abstract

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 ...Continue Reading

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Citations

Jul 26, 2021·Experimental Hematology·Yanan Li, Jeffrey A Magee
Aug 28, 2021·Biomedical Papers of the Medical Faculty of the University Palacký, Olomouc, Czechoslovakia·Romeo Gabriel Mihaila, Diana Topircean

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Datasets Mentioned

BETA
GSE148714

Methods Mentioned

BETA
xenograft
PCR
RNA-seq
Fluorescence
FACS
flow cytometry

Software Mentioned

Ensembl
TreeStar
BBDuk
STAR
BBMap
DESeq2
Rsubread
FACS DIVA
ZEN
FlowJo

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