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FoxO1-dependent induction of acute myeloid leukemia by osteoblasts in mice.

ABSTRACT: Osteoblasts, the bone forming cells, affect self-renewal and expansion of hematopoietic stem cells (HSCs), as well as homing of healthy hematopoietic cells and tumor cells into the bone marrow. Constitutive activation of ?-catenin in osteoblasts is sufficient to alter the differentiation potential of myeloid and lymphoid progenitors and to initiate the development of acute myeloid leukemia (AML) in mice. We show here that Notch1 is the receptor mediating the leukemogenic properties of osteoblast-activated ?-catenin in HSCs. Moreover, using cell-specific gene inactivation mouse models, we show that FoxO1 expression in osteoblasts is required for and mediates the leukemogenic properties of ?-catenin. At the molecular level, FoxO1 interacts with ?-catenin in osteoblasts to induce expression of the Notch ligand, Jagged-1. Subsequent activation of Notch signaling in long-term repopulating HSC progenitors induces the leukemogenic transformation of HSCs and ultimately leads to the development of AML. These findings identify FoxO1 expressed in osteoblasts as a factor affecting hematopoiesis and provide a molecular mechanism whereby the FoxO1/activated ?-catenin interaction results in AML. These observations support the notion that the bone marrow niche is an instigator of leukemia and raise the prospect that FoxO1 oncogenic properties may occur in other tissues.

SUBMITTER: Kode A

PROVIDER: S-EPMC4691220 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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FoxO1-dependent induction of acute myeloid leukemia by osteoblasts in mice.

Kode A A Mosialou I I Manavalan S J SJ Rathinam C V CV Friedman R A RA Teruya-Feldstein J J Bhagat G G Berman E E Kousteni S S

Leukemia 20150625 1

Osteoblasts, the bone forming cells, affect self-renewal and expansion of hematopoietic stem cells (HSCs), as well as homing of healthy hematopoietic cells and tumor cells into the bone marrow. Constitutive activation of β-catenin in osteoblasts is sufficient to alter the differentiation potential of myeloid and lymphoid progenitors and to initiate the development of acute myeloid leukemia (AML) in mice. We show here that Notch1 is the receptor mediating the leukemogenic properties of osteoblast ...[more]

PMID: 26108693

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Project description:ImportanceTests that predict outcomes for patients with acute myeloid leukemia (AML) are imprecise, especially for those with intermediate risk AML.ObjectivesTo determine whether genomic approaches can provide novel prognostic information for adult patients with de novo AML.Design, setting, and participantsWhole-genome or exome sequencing was performed on samples obtained at disease presentation from 71 patients with AML (mean age, 50.8 years) treated with standard induction chemotherapy at a single site starting in March 2002, with follow-up through January 2015. In addition, deep digital sequencing was performed on paired diagnosis and remission samples from 50 patients (including 32 with intermediate-risk AML), approximately 30 days after successful induction therapy. Twenty-five of the 50 were from the cohort of 71 patients, and 25 were new, additional cases.ExposuresWhole-genome or exome sequencing and targeted deep sequencing. Risk of identification based on genetic data.Main outcomes and measuresMutation patterns (including clearance of leukemia-associated variants after chemotherapy) and their association with event-free survival and overall survival.ResultsAnalysis of comprehensive genomic data from the 71 patients did not improve outcome assessment over current standard-of-care metrics. In an analysis of 50 patients with both presentation and documented remission samples, 24 (48%) had persistent leukemia-associated mutations in at least 5% of bone marrow cells at remission. The 24 with persistent mutations had significantly reduced event-free and overall survival vs the 26 who cleared all mutations. Patients with intermediate cytogenetic risk profiles had similar findings. [table: see text].Conclusions and relevanceThe detection of persistent leukemia-associated mutations in at least 5% of bone marrow cells in day 30 remission samples was associated with a significantly increased risk of relapse, and reduced overall survival. These data suggest that this genomic approach may improve risk stratification for patients with AML.

Dataset Information

FoxO1-dependent induction of acute myeloid leukemia by osteoblasts in mice.

Publications

FoxO1-dependent induction of acute myeloid leukemia by osteoblasts in mice.

Similar Datasets

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