Preclinical Efficacy of Tasquinimod-Based Combinations in Advanced Myeloproliferative Neoplasms in Blastic Phase

Authors

Warren Fiskus
Lucia Masarova
Christopher P Mill
Christine E Birdwell
Kaberi Das
Hanxi Hou
John A Davis
Antrix Jain
Anna Malovannaya
Taghi Manshouri
Andrew Dunbar
Surbhi Sharma
Tapan M Kadia
Courtney D DiNardo
Prithviraj Bose
Naveen Pemmaraju
Sanam Loghavi
Xiaoping Su
Raajit K Rampal
Marie Törngren
Kapil N Bhalla

Language

English

Publication Date

11-11-2025

Journal

Blood Advances

DOI

10.1182/bloodadvances.2025016898

PMID

40829105

PMCID

PMC12630344

PubMedCentral® Posted Date

8-21-2025

PubMedCentral® Full Text Version

Post-print

Abstract

The alarmins, S100A8 (A8) and S100A9 (A9), are low molecular weight proteins belonging to the S100 protein family. A8 and A9 are secreted into the extracellular space and plasma, in which they interact with Toll-like receptor 4, receptor for advanced glycation end products, and CD33. In these studies, we determined the preclinical efficacy of tasquinimod (TQ) against advanced myeloproliferative neoplasm (MPN) cell lines and patient-derived (PD) CD34+ blastic phase (BP; >5% blasts in the peripheral blood) MPN cells. TQ induced loss of viability in cell lines and PD MPN-BP cells, but not in normal CD34+ progenitor cells. In TQ-treated PD MPN-acute myeloid leukemia (AML) cells, RNA-sequencing analysis showed negative enrichment of the gene sets of MYC and E2F targets, interleukin-6-JAK-STAT3 signaling, and of inflammatory response. In phenotypically defined, PD CD34+ MPN-BP stem progenitor cells, cytometry by time-of-flight analysis showed that TQ reduced expression of proteins including A8, A9, and myeloperoxidase, while increasing expression of Growth Factor Independence 1 (GFI1), p21, and cleaved Poly(ADP-ribose) polymerase (PARP). Cotreatment with TQ and ruxolitinib or Bromodomain and extraterminal domain (BET) inhibitor induced synergistic lethality in advanced MPN-BP cells. Monotherapy with TQ significantly improved survival of immune-depleted NOD scid gamma (NSG) mice engrafted with PD xenograft (PDX) cells of MPN-AML. Notably, cotreatment with TQ and ruxolitinib or OTX015 induced significantly greater survival than treatment with single agents in the NSG mice engrafted with the PDX cells. These findings clearly demonstrate the preclinical efficacy of TQ in advanced MPN-BP cells and create the rationale to further interrogate the efficacy of TQ-based combinations with the current, frontline therapies or novel agents in advanced MPNs with excess blasts.

Keywords

Humans, Animals, Myeloproliferative Disorders, Mice, Quinolones, Blast Crisis, Cell Line, Tumor, Antineoplastic Combined Chemotherapy Protocols, Xenograft Model Antitumor Assays

Published Open-Access

yes

Recommended Citation

Fiskus, Warren; Masarova, Lucia; Mill, Christopher P; et al., "Preclinical Efficacy of Tasquinimod-Based Combinations in Advanced Myeloproliferative Neoplasms in Blastic Phase" (2025). Faculty and Staff Publications. 4923.
https://digitalcommons.library.tmc.edu/baylor_docs/4923