Activin A contributes to the definition of a pro-oncogenic bone marrow microenvironment in t(12;21) preleukemia

Portale, Federica; Beneforti, Linda; Fallati, Alessandra; Biondi, Andrea; Palmi, Chiara; Cazzaniga, Giovanni; Dander, Erica; D’Amico, Giovanna

doi:10.1016/j.exphem.2019.02.006

Cited by 10 publications

(15 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Our results uncover an essential mechanism involving the proinflammatory cytokine IL-6 in sustaining Pax5-dependent B-ALL development. Abnormal profiles of inflammatory markers, including higher concentrations of IL-6, IL-17, and IL-18, have already been detected in neonatal blood spot samples of children who later developed B-cell precursor ALL 34 , and in vitro studies have also shown that pro-inflammatory cytokines like IL-6/IL-1β/ TNFα 35 or TGF-β dependent signaling 36,37 , can predispose pre-leukemic B cells to malignant transformation. However, the real contribution of these inflammatory pathways to B-ALL development remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of inflammatory signaling in Pax5 mutant cells mitigates B-cell leukemogenesis

Isidro-Hernández

Mayado²,

Casado-García

et al. 2020

Sci Rep

Self Cite

View full text Add to dashboard Cite

PAX5 is one of the most frequently mutated genes in B-cell acute lymphoblastic leukemia (B-ALL), and children with inherited preleukemic PAX5 mutations are at a higher risk of developing the disease. Abnormal profiles of inflammatory markers have been detected in neonatal blood spot samples of children who later developed B-ALL. However, how inflammatory signals contribute to B-ALL development is unclear. Here, we demonstrate that Pax5 heterozygosis, in the presence of infections, results in the enhanced production of the inflammatory cytokine interleukin-6 (IL-6), which appears to act in an autocrine fashion to promote leukemia growth. Furthermore, in vivo genetic downregulation of IL-6 in these Pax5 heterozygous mice retards B-cell leukemogenesis, and in vivo pharmacologic inhibition of IL-6 with a neutralizing antibody in Pax5 mutant mice with B-ALL clears leukemic cells. Additionally, this novel IL–6 signaling paradigm identified in mice was also substantiated in humans. Altogether, our studies establish aberrant IL6 expression caused by Pax5 loss as a hallmark of Pax5-dependent B-ALL and the IL6 as a therapeutic vulnerability for B-ALL characterized by PAX5 loss.

show abstract

Section: Discussionmentioning

confidence: 99%

Inhibition of inflammatory signaling in Pax5 mutant cells mitigates B-cell leukemogenesis

Isidro-Hernández

Mayado²,

Casado-García

et al. 2020

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…Accordingly, we showed that transforming growth factor β (TGFβ), a pleiotropic cytokine produced during inflammation by several stromal and immune cells [ 49 ] and activin A, another member of the TGFβ family secreted by MSCs after exposure to pro-inflammatory stimuli, favored the emergence of ETV6-RUNX1 pre-leukemic cells over their normal counterparts in competitive growth assays [ 16 , 50 ]. In brief, we demonstrated that the fusion gene associates with the intracellular signal transducer SMAD3 preventing its signaling in the case of TGFβ/activin pathway activation [ 16 ].…”

Section: The Role Of the Microenvironment In The Transition From Pre-leukemia To Overt Leukemiamentioning

confidence: 99%

“…In brief, we demonstrated that the fusion gene associates with the intracellular signal transducer SMAD3 preventing its signaling in the case of TGFβ/activin pathway activation [ 16 ]. As a consequence, while these two cytokines inhibit the proliferation of normal progenitor B cells, they have minor effects on the pre-leukemic ETV6-RUNX1+ cells, thus facilitating the competitive expansion of the latter [ 16 , 50 ].…”

Section: The Role Of the Microenvironment In The Transition From Pre-leukemia To Overt Leukemiamentioning

confidence: 99%

“…Several reports indicate that leukemic cells can specifically migrate in response to MSC-derived CXCL12 in an amount-specific manner and that this migration can be inhibited by the CXCR4 antagonist AMD3100 [ 62 , 65 , 66 ]. Even if B-ALL cells in vitro co-cultured with HD-MSCs did not directly modulate CXCL12 secretion by MSCs [ 62 ], our group recently demonstrated that Activin A, a soluble mediator belonging to the TGFβ family, overexpressed in the B-ALL BM niche [ 63 ], is able to downregulate CXCL12 production by BM-MSCs [ 50 ]. Moreover, Activin A was demonstrated to significantly enhance in vitro the migration of B-ALL cells in response to CXCL12, even if present at very low doses, while inhibiting the migration of healthy CD34 + cells [ 63 ].…”

Section: The Bm Niche In Overt B-all: a Corrupted Microenvironment Reprogrammed To Sustain Leukemic Cellsmentioning

confidence: 99%

“…The production of this molecule was specifically driven by leukemia, since primary B-ALL cells induced a significant increase in Activin A release upon co-culture with HD-MSCs. Interestingly, as described in the previous paragraph, Activin A was demonstrated on the one hand to directly act on leukemic cells by enhancing their migratory and invasive properties, both in vitro and in a xenograft mouse model [ 63 ], and on the other hand by down-modulating CXCL12 production by HD-MSC [ 50 ].…”

Section: The Bm Niche In Overt B-all: a Corrupted Microenvironment Reprogrammed To Sustain Leukemic Cellsmentioning

confidence: 99%

See 2 more Smart Citations

The Bone Marrow Niche in B-Cell Acute Lymphoblastic Leukemia: The Role of Microenvironment from Pre-Leukemia to Overt Leukemia

Dander

Palmi

D’Amico

et al. 2021

IJMS

Self Cite

View full text Add to dashboard Cite

Genetic lesions predisposing to pediatric B-cell acute lymphoblastic leukemia (B-ALL) arise in utero, generating a clinically silent pre-leukemic phase. We here reviewed the role of the surrounding bone marrow (BM) microenvironment in the persistence and transformation of pre-leukemic clones into fully leukemic cells. In this context, inflammation has been highlighted as a crucial microenvironmental stimulus able to promote genetic instability, leading to the disease manifestation. Moreover, we focused on the cross-talk between the bulk of leukemic cells with the surrounding microenvironment, which creates a “corrupted” BM malignant niche, unfavorable for healthy hematopoietic precursors. In detail, several cell subsets, including stromal, endothelial cells, osteoblasts and immune cells, composing the peculiar leukemic niche, can actively interact with B-ALL blasts. Through deregulated molecular pathways they are able to influence leukemia development, survival, chemoresistance, migratory and invasive properties. The concept that the pre-leukemic and leukemic cell survival and evolution are strictly dependent both on genetic lesions and on the external signals coming from the microenvironment paves the way to a new idea of dual targeting therapeutic strategy.

show abstract

Immune stress suppresses innate immune signaling in preleukemic precursor B-cells to provoke leukemia in predisposed mice

Isidro-Hernández,

Casado-García,

Oak

et al. 2023

Nat Commun

View full text Add to dashboard Cite

The initial steps of B-cell acute lymphoblastic leukemia (B-ALL) development usually pass unnoticed in children. Several preclinical studies have shown that exposure to immune stressors triggers the transformation of preleukemic B cells to full-blown B-ALL, but how this takes place is still a longstanding and unsolved challenge. Here we show that dysregulation of innate immunity plays a driving role in the clonal evolution of pre-malignant Pax5+/− B-cell precursors toward leukemia. Transcriptional profiling reveals that Myd88 is downregulated in immune-stressed pre-malignant B-cell precursors and in leukemic cells. Genetic reduction of Myd88 expression leads to a significant increase in leukemia incidence in Pax5+/−Myd88+/− mice through an inflammation-dependent mechanism. Early induction of Myd88-independent Toll-like receptor 3 signaling results in a significant delay of leukemia development in Pax5+/− mice. Altogether, these findings identify a role for innate immunity dysregulation in leukemia, with important implications for understanding and therapeutic targeting of the preleukemic state in children.

show abstract

Activin A contributes to the definition of a pro-oncogenic bone marrow microenvironment in t(12;21) preleukemia

Cited by 10 publications

References 21 publications

Inhibition of inflammatory signaling in Pax5 mutant cells mitigates B-cell leukemogenesis

Inhibition of inflammatory signaling in Pax5 mutant cells mitigates B-cell leukemogenesis

The Bone Marrow Niche in B-Cell Acute Lymphoblastic Leukemia: The Role of Microenvironment from Pre-Leukemia to Overt Leukemia

Immune stress suppresses innate immune signaling in preleukemic precursor B-cells to provoke leukemia in predisposed mice

Contact Info

Product

Resources

About