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

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Hematopoietic Stem Cells Are Intrinsically Protected against MLL-ENL-Mediated Transformation. / Ugale, Amol; Norddahl, Gudmundur; Wahlestedt, Martin; Säwén, Petter; Jaako, Pekka; Pronk, Kees-Jan; Soneji, Shamit; Cammenga, Jörg; Bryder, David.

I: Cell Reports, Vol. 9, Nr. 4, 2014, s. 1246-1255.

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T1 - Hematopoietic Stem Cells Are Intrinsically Protected against MLL-ENL-Mediated Transformation.

AU - Ugale, Amol

AU - Norddahl, Gudmundur

AU - Wahlestedt, Martin

AU - Säwén, Petter

AU - Jaako, Pekka

AU - Pronk, Kees-Jan

AU - Soneji, Shamit

AU - Cammenga, Jörg

AU - Bryder, David

N1 - 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)

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

U2 - 10.1016/j.celrep.2014.10.036

DO - 10.1016/j.celrep.2014.10.036

M3 - Article

VL - 9

SP - 1246

EP - 1255

JO - Cell Reports

T2 - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 4

ER -