Therapeutically targeting <scp>SELF</scp>‐reinforcing leukemic niches in acute myeloid leukemia: A worthy endeavor?

Bernasconi, Paolo; Farina, Mirko; Boni, Marina; Dambruoso, Irene; Calvello, Celeste

doi:10.1002/ajh.24312

Cited by 20 publications

(17 citation statements)

References 144 publications

(167 reference statements)

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“…Besides the direct impact of activated Notch signaling on LSC and HSC, the augmented proliferation and infiltration of LSC compared to normal HSC could be favorable for their competition for the niche over HSC. Various studies have demonstrated that LSC could positively remodel the BM microenvironment to enhance support of LSC at the expense of HSC, 47 , 48 and this remodeling may in turn further promote leukemia progression and impair normal hematopoiesis. In addition, the reduced expression of Cxcl12 , Scf and Angpt1 in Twist1 -deleted mice may also account for the opposing impact of Twist1 deletion on HSC and LSC, since compared with HSC, LSC are less factor-dependent.…”

Section: Discussionmentioning

confidence: 99%

Niche TWIST1 is critical for maintaining normal hematopoiesis and impeding leukemia progression

Liu

et al. 2018

Haematologica

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The bone marrow microenvironment regulates normal and malignant hematopoiesis, but the underlying molecular mechanisms remain poorly defined. Using a chimeric mice model, we demonstrate that Twist1 deletion in the bone marrow microenvironment results in alteration of multiple niche cells as well as downregulated expression of major hematopoietic stem cell supportive factors. The perturbed microenvironment reduces hematopoietic stem cell homing and retention, impairs hematopoietic stem cell self-renewal and induces myeloid skewing. Nevertheless, it accelerates the progression of MLL-AF9 leukemia, which is partially mediated by Jagged-2-dependent Notch signaling. Our data provide the first demonstration of a pivotal role of TWIST1 in favoring normal hematopoiesis and hampering leukemia development. They also bring new insights into the role of the bone marrow niche in driving the development of acute myeloid leukemia, and suggest possible new avenues, exploiting the niche, to improve leukemia treatments.

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Section: Discussionmentioning

confidence: 99%

Niche TWIST1 is critical for maintaining normal hematopoiesis and impeding leukemia progression

Liu

et al. 2018

Haematologica

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“…Therefore, in order to develop targeted therapies with clinical efficacy, it will be critical to identify unifying mechanisms required for AML progression, irrespective of the diverse genetic and molecular abnormalities. In vitro functional analyses have aided these drug discovery efforts (Tibes et al, 2012), but are commonly conducted in the absence of microenvironmental factors such as secreted cytokines and growth factors known to influence cell survival and response to therapy (Bernasconi et al, 2016). …”

Section: Introductionmentioning

confidence: 99%

Identification of Interleukin-1 by Functional Screening as a Key Mediator of Cellular Expansion and Disease Progression in Acute Myeloid Leukemia

et al. 2017

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Summary Secreted proteins in the bone marrow microenvironment play critical roles in acute myeloid leukemia (AML). Through an ex vivo functional screen of 94 cytokines, we identified that the pro-inflammatory cytokine interleukin-1 (IL-1) elicited profound expansion of myeloid progenitors in ~67% of AML patients while suppressing the growth of normal progenitors. Levels of IL-1β and IL-1 receptors were increased in AML patients, and silencing of the IL-1 receptor led to significant suppression of clonogenicity and in vivo disease progression. IL-1 promoted AML cell growth by enhancing p38MAPK phosphorylation and promoting secretion of various other growth factors and inflammatory cytokines. Treatment with p38MAPK inhibitors reversed these effects and recovered normal CD34+ cells from IL-1-mediated growth suppression. These results highlight the importance of ex vivo functional screening to identify common and actionable extrinsic pathways in genetically heterogeneous malignancies and provide impetus for clinical development of IL-1/IL1R1/p38MAPK pathway-targeted therapies in AML.

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“…Thus, there is a need for identification of new therapeutic targets and development of new therapeutic strategies that are more efficient and better tolerated [22]. Targeting of the bidirectional communication between AML cells and their neighboring leukemia-supporting stromal cells is a possible approach [23,24,25,26,27,28]. In a previous study investigating another patient cohort, we described that high constitutive mediator release is associated with better long-term overall survival compared with low constitutive release [29].…”

Section: Introductionmentioning

confidence: 99%

High Constitutive Cytokine Release by Primary Human Acute Myeloid Leukemia Cells Is Associated with a Specific Intercellular Communication Phenotype

Reikvam

Aasebø

Brenner

et al. 2019

JCM

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Acute myeloid leukemia (AML) is a heterogeneous disease, and this heterogeneity includes the capacity of constitutive release of extracellular soluble mediators by AML cells. We investigated whether this capacity is associated with molecular genetic abnormalities, and we compared the proteomic profiles of AML cells with high and low release. AML cells were derived from 71 consecutive patients that showed an expected frequency of cytogenetic and molecular genetic abnormalities. The constitutive extracellular release of 34 soluble mediators (CCL and CXCL chemokines, interleukins, proteases, and protease regulators) was investigated for an unselected subset of 62 patients, and they could be classified into high/intermediate/low release subsets based on their general capacity of constitutive secretion. FLT3-ITD was more frequent among patients with high constitutive mediator release, but our present study showed no additional associations between the capacity of constitutive release and 53 other molecular genetic abnormalities. We compared the proteomic profiles of two contrasting patient subsets showing either generally high or low constitutive release. A network analysis among cells with high release levels demonstrated high expression of intracellular proteins interacting with integrins, RAC1, and SYK signaling. In contrast, cells with low release showed high expression of several transcriptional regulators. We conclude that AML cell capacity of constitutive mediator release is characterized by different expression of potential intracellular therapeutic targets.

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Therapeutically targeting SELF‐reinforcing leukemic niches in acute myeloid leukemia: A worthy endeavor?

Cited by 20 publications

References 144 publications

Niche TWIST1 is critical for maintaining normal hematopoiesis and impeding leukemia progression

Niche TWIST1 is critical for maintaining normal hematopoiesis and impeding leukemia progression

Identification of Interleukin-1 by Functional Screening as a Key Mediator of Cellular Expansion and Disease Progression in Acute Myeloid Leukemia

High Constitutive Cytokine Release by Primary Human Acute Myeloid Leukemia Cells Is Associated with a Specific Intercellular Communication Phenotype

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