Hematopoietic Stem Cells Are Intrinsically Protected against MLL-ENL-Mediated Transformation.

Amol Ugale, Gudmundur Norddahl, Martin Wahlestedt, Petter Säwén, Pekka Jaako, Kees-Jan Pronk, Shamit Soneji, Jörg Cammenga, David Bryder

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskriftPeer review

445 Nedladdningar (Pure)

Sammanfattning

Studies of developmental pathways of hematopoietic stem cells (HSCs) have defined lineage relationships throughout the blood system. This is relevant to acute myeloid leukemia (AML), where aggressiveness and therapeutic responsiveness can be influenced by the initial stage of transformation. To address this, we generated a mouse model in which the mixed-lineage leukemia/eleven-nineteen-leukemia (MLL-ENL) transcription factor can be conditionally activated in any cell type. We show that AML can originate from multiple hematopoietic progenitor subsets with granulocytic and monocytic potential, and that the normal developmental position of leukemia-initiating cells influences leukemic development. However, disease failed to arise from HSCs. Although it maintained or upregulated the expression of target genes associated with leukemic development, MLL-ENL dysregulated the proliferative and repopulating capacity of HSCs. Therefore, the permissiveness for development of AML may be associated with a narrower window of differentiation than was previously appreciated, and hijacking the self-renewal capacity of HSCs by a potent oncogene is insufficient for leukemic development.
Originalspråkengelska
Sidor (från-till)1246-1255
TidskriftCell Reports
Volym9
Nummer4
DOI
StatusPublished - 2014

Bibliografisk information

The information about affiliations in this record was updated in December 2015.
The record was previously connected to the following departments: Division of Molecular Medicine and Gene Therapy (013022010), Stem Cell Aging (013212073)

Ämnesklassifikation (UKÄ)

  • Cellbiologi

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