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The age of the hematopoietic microenvironment specifies lineage in MLL-rearranged leukemia [Ccl5]

ABSTRACT: The defining characteristics of leukemia, such as lineage and genetics, are associated with a typical age of onset. Understanding mechanisms of leukemia age specificity could improve disease models to develop new therapies. We used heterochronic transplantation of murine leukemia driven by MLL-AF9 to investigate the relative contribution of the age of the cell-of-origin or the hematopoietic microenvironment to the lineage fate of leukemia initiating cells (LICs). We show that the neonatal hematopoietic niche supports the development of infant-like mixed lineage B-cell/myeloid leukemia, while a mature niche promotes adult-like pure acute myeloid leukemia (AML) from identical cells of origin. We attribute this to inhibition of B-lymphoid fate in multipotent progenitor-like LICs by Ccl5 from adult bone marrow (BM) stroma, and implicate glycogen synthase kinase-3 (GSK-3) signaling in the myeloid fate specification in mouse and human MLL-driven leukemia. These findings connect maturation and aging of the hematopoietic system to leukemia age specificity.

ORGANISM(S): Mus musculus

PROVIDER: GSE105086 | GEO | 2019/01/29

REPOSITORIES: GEO

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Project description:Acute myeloid leukemia (AML) propagates as a cellular hierarchy which is maintained by a rare subpopulation of self-renewing leukemia-initiating cells (LICs). These LICs phenotypically resemble HSCs and early myeloid progenitors, and they are functionally defined by their ability to reconstitute AML in xenografted mice. Common transcriptional regulators are believed to drive self-renewal of LICs and normal stem cells. Examples include the histone methyltransferase, MLL and its main targets, the transcription factors HOXA9 and MEIS1; the polycomb group protein, BMI-1; and the Wnt/β-catenin signaling pathway4-9. In AML patients, LICs have been shown to share broad gene expression signatures with hematopoietic stem cells (HSCs) and, in some cases, with embryonic stem cells (ESCs). Moreover, increased expression of these stem cell signatures has been linked to tumor aggressiveness. Elucidating the molecular determinants of stem cell properties in LICs has the potential to improve AML therapy and clarify the relationship between cancer and stem cell biology in general. Here we show that the propagation of LICs in AML depends on Zfx, a transcription factor required for the self-renewal of ESCs and HSCs. Using mouse models, we found that Zfx is required for AML propagation and LIC maintenance. We defined a Zfx-driven gene expression program in murine LICs that correlates with existing stem cell-related gene expression signatures in AML patients. Using a novel, stroma-based RNAi screening strategy, we identified functionally important Zfx target genes. Two of these genes – FAM92A1 and DOCK7 - are required for human AML cell propagation; moreover, their expression levels strongly correlate with AML patient survival across the full spectrum of AML subtypes. Together, our results characterize a novel gene expression program that orchestrates critical stem cell properties of LICs, and drives aggressiveness of AML. Independent primary MLL-AF9 AML cell lines were created carrying the tamoxifen inducible Cre-ER transgene and either the Zfx wild-type (wt/y) (lines 10977, 10980) or the Zfx conditional (Zfx fl/y) allele (lines 10949, 10950, 10986). AML cells generated from each line were isolated from moribund mice and cultured with or without 4-hydroxytamoxifen for 72 hours to induce Cre. After Cre induction, c-Kit + cells were purified by FACS and processed for microarray studies.

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The age of the hematopoietic microenvironment specifies lineage in MLL-rearranged leukemia [Ccl5]

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