HOXA9 overexpression

The miR-140-3p-HOXA9 signaling disruption is closely linked to lymph node metastasis and unfavorable prognosis in CRC. This axis shows promise as a clinical biomarker for predicting the CRC patient survival and a potential therapeutic target.

P1, N=44, Active, not recruiting, Northwestern University | Recruiting --> Active, not recruiting | Trial completion date: Jan 2024 --> Jan 2027 | Trial primary completion date: Mar 2023 --> Dec 2025

The BH3 mimetic venetoclax, in combination with low dose cytarabine, decitabine or azacitidine has shown clinical efficacy in newly diagnosed acute myeloid leukemia (AML) (1, 2). We also demonstrate that neutrophils can be recovered using IL-3 neutralisation in combination with venetoclax in AML engrafted mice. Taken together, these findings provide biologic insight for IL-3 inhibition alongside venetoclax to reduce the incidence of cytopenias observed in elderly AML patients.

This study showed that HOXA9 expression was associated with chemotherapy resistance and poor outcomes in HGSOC patients. High HOXA9 expression might be a prognostic indicator for HGSOC.

Recent studies reveal that the dNTP and Ara-CTP (active form of cytarabine) hydrolase SAMHD1, whose loss-of-function mutation is seen in inflammatory encephalopathy named Aicardi-Goutières syndrome, limits type-1 Interferon (IFN-I) and T cell responses by suppressing cGAS/STING signaling...To determine if immune activation requires SAMHD1 catalysis, we knocked out endogenous SAMHD1 in THP1 cells, which we then engineered cells to express doxycycline-inducible SAMHD1 variants including WT (SAMWT), catalytically-dead mutant SAMHD1 (SAMMT) or empty vector (MOCK)...These results suggest that SAMHD1 plays an oncogenic role in AML by suppressing innate immunity. Further analysis is required to determine whether our compound can ablate AML in vivo when combined with currently available immune checkpoint inhibitors.

Moreover, the dihydroorotate dehydrogenase (DHODH) inhibitor that reduces leukaemogenesis in mammals effectively restored haematopoiesis in Tg(drl:hoxa9;hsp70:meis1) embryos and improved their late survival. Thus, Tg(drl:hoxa9;hsp70:meis1) zebrafish is a rapid-onset high-penetrance AML-like disease model, which provides a novel tool to harness the unique advantages of zebrafish for mechanistic studies and drug screening against HOXA9/MEIS1 overexpressed high-risk AML.

These findings indicate that the expression of HOXA9 and its functional network is regulated by RA signaling in normal colonic SCs, and, when dysregulated, HOXA9 may contribute to CSC overpopulation that drives CRC development and growth. Our study provides a regulatory mechanism that might be useful in developing treatments against CSC overpopulation in CRC.

Finally, overexpression of HOXA9 was shown to partially reverse the tumor promoting effect of miR-19b-3p. This study indicates that miR-19b-3p is a crucial prognostic biomarker of NSCLC, and that targeting of the miR-19b-3p/HOXA9 axis may be a promising strategy in NSCLC therapy.

Thus, our results show that HOXA9 is regulated by RA signaling and when dysregulated, contributes to CRC development and growth. These findings provide a mechanism that may be targeted in the design of novel treatments against SC overpopulation in CRC.

Cmpd 41 also demonstrated superior in vivo anti-leukemic activity in multiple AML xenograft models as monotherapy and demonstrated synergy with a hypomethylating agent, decitabine in TP53 mutated AML...In summary, we introduce a best in class DHODH inhibitor with a data-driven combination strategy for both AML and MM. Our studies suggest a highly synergistic combination strategy involving immunotherapy for AML and other hematologic malignancies.

Greater than or equal to 100 (HR =2.31, 95% CI: 1.54-3.45, P<0.0001) and less than 100 (HR =2.45, 95% CI: 1.42-4.23, P=0.001). HOXA9 methylation has a significantly estimable biomarker of predicting poor prognosis and a potential target for therapy in solid malignant carcinoma from our meta-analysis.

The results of dual-luciferase reporter gene showed that expression and activity of HOXA9 were downregulated accordingly, and the level of HOXA9 protein was decreased with enhancing miR-652 expression (P < 0.01). miR-652 may negatively regulate HOXA9 expression and inhibit the proliferation, migration, and invasion abilities of osteosarcoma cells through the PI3K/Akt signaling pathway.

Moreover, AACOCF3 was highly active in human AML with MLL rearrangement, in which PLA2G4A was significantly higher expressed than in AML patients without MLL rearrangement, and is sufficient as an independent prognostic marker. Our work, thus, identifies PLA2G4A as a prognostic marker and potential therapeutic target for H9M-dependent AML with MLL-rearrangement.

Using mouse xenografts, we demonstrated that hypermethylated T-ALL samples exhibited therapeutic responses to the DNA hypomethylating agent 5-azacytidine, which significantly (survival probability; P = 0.001 for C, 0.01 for C, and 0.0253 for C) delayed tumor progression. These findings suggest that epigenetic-based therapies may provide an alternative treatment option in hypermethylated T-ALL.

In multivariate analysis, HOXA9 over-expression independently and significantly predicted poorer PFS (p < 0.01, hazard ratio (HR) = 2.387, 95% CI &lsqb;0.876, 6.545]) and OS (p < 0.01, HR = 2.486, 95% CI &lsqb;1.041, 8.926]). High HOXA9 expression is an independent prognostic factor associated with advanced tumour stage and poorer survival in NPC patients.

DB818 has potential as a novel molecular targeted drug for treating AML associated with HOXA9 overexpression.

Taken together, higenamine could be employed as a starting point for the development of more selective and potent LSD1 inhibitors. Our work firstly reveals the non-classical epigenetic regulation mechanism of higenamine in cancers, and also demonstrates the efficacy of higenamine for MLL-rearranged leukemia therapy.

CPP33-HADP effectively reduced the invasion ability of NSCLC cells in both in vitro and in vivo mouse models. Our results suggest that CPP33-HADP has significant potential for therapeutic applications in metastatic NSCLC.

Moreover, alteration of CTCF boundaries in the oncogene loci may provide a novel strategy to overcome the drug resistance of LSCs. Graphical abstract.

Cut&Run analysis revealed the direct occupancy of USF2 at HOXA9 promoter in MLLr leukemia cells. Collectively, the HOXA9 reporter facilitated the functional interrogation of the HOXA9 regulome and has advanced our understanding of the molecular regulation network in HOXA9-driven leukemia.

P1, N=44, Recruiting, Northwestern University | Trial completion date: Jan 2021 --> Jan 2024 | Trial primary completion date: Mar 2020 --> Mar 2023