Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2020.02.26.967018

TIRAP drives myelosuppression through an Ifnγ-Hmgb1 axis that disrupts the marrow microenvironment

Ibrahim, R.·Gopal, A.·Fuller, M.·Umlandt, P.·Chang, L.·Wegrzyn-Woltosz, J.·Lam, J.·Li, J.·Lu, M.·Parker, J.·Karsan, A.
View original source ↗Export metadata ↓

Abstract

Activation of inflammatory pathways is associated with bone marrow failure syndromes, but how specific molecules impact on the marrow microenvironment is not well elucidated. We report a novel role for the miR-145 target, Toll/Interleukin-1 receptor domain containing adaptor protein (TIRAP), in driving bone marrow failure. We show that TIRAP is overexpressed in various types of myelodysplastic syndromes (MDS), and suppresses all three major hematopoietic lineages.. Constitutive expression of TIRAP in hematopoietic stem/progenitor cells (HSPC) promotes upregulation of Ifn{gamma}, leading to bone marrow failure. Myelopoiesis is suppressed through Ifn{gamma}-Ifn{gamma}r-mediated release of the alarmin, Hmgb1, which disrupts the marrow endothelial niche. Deletion of Ifn{gamma} or Ifn{gamma}r blocks Hmgb1 release and is sufficient to reverse the endothelial defect and prevent myelosuppression. In contrast, megakaryocyte and erythroid production is repressed independently of the Ifn{gamma} receptor. Contrary to current dogma, TIRAP-activated Ifn{gamma}-driven marrow suppression is independent of T cell function or pyroptosis. In the absence of Ifn{gamma}, TIRAP drives myeloproliferation, implicating Ifn{gamma} in suppressing the transformation of bone marrow failure syndromes to myeloid malignancy. These findings reveal novel, non-canonical roles of TIRAP, Hmgb1 and Ifn{gamma} function in the marrow microenvironment,and provide insight into the pathophysiology of preleukemic syndromes. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=165 SRC="FIGDIR/small/967018v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@d033fborg.highwire.dtl.DTLVardef@104bab9org.highwire.dtl.DTLVardef@17ed484org.highwire.dtl.DTLVardef@1b228ed_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract: Model of proposed mechanism of TIRAP-induced BMFConstitutive TIRAP expression in marrow cells releases Ifn{gamma}, which directly impacts on megakaryocyte and erythroid production, but indirectly suppresses myelopoiesis through the release of the alarmin, Hmgb1, which disrupts the marrow endothelial compartment. C_FIG

Source connections

Explore related subjects

cancer biologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Ibrahim, R., Gopal, A., Fuller, M., Umlandt, P., Chang, L., Wegrzyn-Woltosz, J., Lam, J., Li, J., Lu, M., Parker, J., Karsan, A.. 2020-02-28. TIRAP drives myelosuppression through an Ifnγ-Hmgb1 axis that disrupts the marrow microenvironment. https://doi.org/10.1101/2020.02.26.967018

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

The methionine cycle sustains the mesenchymal phenotype of tumor cells and drives PDA progression

Mesenchymal traits are associated with poor prognosis in Pancreatic Ductal Adenocarcinoma (PDA), but direct targeting of mesenchymal tumor cells remains a challenge. Metabolic profiling of tumor cells isolated from murine PDA and liver metastases (LM) revealed that LM rely more on the methionine cycle than does primary PDA. This metabolic shift was specifically associated with increased activation of the methionine cycle in mesenchymal tumor cells compared to differentiated tumor cells. We show that the targeting of the key enzyme of the methionine cycle S-adenosylhomocysteine hydrolase (SAHH) in mesenchymal cells lowers the levels of homocysteine (Hcy) and glutathione, resulting in reduced antioxidant capacity, deregulated intracellular calcium homeostasis, and ultimately loss of mesenchymal markers. Together, these events decrease cell proliferation and invasion, blunting the tumorigenic and metastatic potential of SAHH-deficient cells, eventually impeding tumor growth and progression of the metastatic disease. Clinically, the high expression of SAHH in patients with mesenchymal PDA is correlated with poor survival, positioning SAHH as a potential therapeutic target to impede the pro-metastatic, mesenchymal phenotype of PDA.

cancer biology↗
bioRxiv2026

Arrest-associated transcriptional programmes outweigh apoptosis-associated programmes in treatment-naive pancreatic ductal adenocarcinoma

Background: Pancreatic ductal adenocarcinoma (PDAC) is driven by mutant KRAS, and RAS inhibitors now extend survival in previously treated metastatic disease. Whether treatment shrinks a tumour or only halts its growth depends partly on whether cancer cells die or stop dividing, yet how untreated PDAC cells are balanced between these programmes is unknown. Aims: We aimed to characterise the balance between apoptosis-associated and arrest-associated transcriptional programmes in treatment-naive PDAC and to examine their relationships with tumour subtype, TGM2 expression, tissue organisation, survival and drug sensitivity. Methods and results: We scored 52,999 malignant cells from 18 untreated patients in the Hwang atlas using a transcriptional contrast between genes associated with apoptosis and genes associated with resistance to apoptosis or cell-cycle arrest. In every patient the contrast was shifted toward the arrest-associated side: using equality between the two sides as the dividing threshold, 86.3% of cells with an informative score fell on that side, although the proportion depends on the threshold chosen. The shift recurred in the independent Steele atlas (median 71.6% per sample, range 37.1% to 90.8%). In the discovery cohort, tumours with higher basal-like scores had fewer arrest-side cells, and TGM2 expression was modestly higher on the arrest-associated side in both cohorts. The contrast did not track cell-line drug sensitivity or survival in bulk tumours. Conclusion: Untreated PDAC cells show a reproducible transcriptional bias toward anti-apoptotic and cell-cycle-arrest programmes. Whether this bias predicts cellular responses to treatment remains to be tested.

cancer biology↗
bioRxiv2026

Quantitative live imaging reveals region-dependent medulloblastoma disseminationin the zebrafish brain

Medulloblastoma is the most common malignant pediatric brain tumor, and relapse is frequently driven by dissemination within the central nervous system. Yet the early dynamics of tumor spread remain difficult to resolve in vivo. Here, we orthotopically transplanted human medulloblastoma cells into larval zebrafish and followed individual xenografts by longitudinal high-resolution confocal imaging. ONS-76 showed particularly robust dissemination, with hindbrain tumors spreading into the developing cerebellum in 81.5% of larvae, more than fourfold the frequency observed for forebrain or midbrain tumors. Disseminating cells extended along brain-surface and leptomeningeal-like regions and frequently associated with cerebral vasculature. Quantitative analysis of tumor area, perimeter, compactness, convex hull area, and fractal dimension captured changes in growth and spatial complexity over time. Dasatinib reduced tumor expansion and dissemination-related features in a concentration-dependent manner, while higher doses revealed host toxicity. These findings establish a powerful in vivo model for resolving medulloblastoma dissemination and therapeutic response.

cancer biology↗