Novel Compounds Synergize With Venetoclax to Target KMT2A-Rearranged Pediatric Acute Myeloid Leukemia

Abstract

In pediatric acute myeloid leukemia (AML), fusions involving lysine methyltransferase 2A (KMT2A) are considered hallmarks of aggressive AML, for whom the development of targeted specific therapeutic agents to ameliorate classic chemotherapy and obtain a complete eradication of disease is urgent. In this study, we investigated the antiapoptotic proteins in a cohort of 66 pediatric AML patients, finding that 75% of the KMT2A-r are distributed in Q3 + Q4 quartiles of BCL-2 expression, and KMT2A-r have statistically significant high levels of BCL-2, phospho-BCL-2 S70, and MCL-1, indicating a high anti-apoptotic pathway activation. In an attempt to target it, we tested novel drug combinations of venetoclax, a B-cell lymphoma-2 (BCL-2) inhibitor, in KMT2A-MLLT3, for being the most recurrent, and KMT2A-AFDN, for mediating the worst prognosis, rearranged AML cell lines. Our screening revealed that both the bromodomain and extra-terminal domain (BET) inhibitor, I-BET151, and kinase inhibitor, sunitinib, decreased the BCL-2 family protein expression and significantly synergized with venetoclax, enhancing KMT2A-r AML cell line death. Blasts t (6; 11) KMT2A-AFDN rearranged, both from cell lines and primary samples, were shown to be significantly highly responsive to the combination of venetoclax and thioridazine, with the synergy being induced by a dramatic increase of mitochondrial depolarization that triggered blast apoptosis. Finally, the efficacy of novel combined drug treatments was confirmed in KMT2A-r AML cell lines or ex vivo primary KMT2A-r AML samples cultured in a three-dimensional system which mimics the bone marrow niche. Overall, this study identified that, by high-throughput screening, the most KMT2A-selective drugs converged in different but all mitochondrial apoptotic network activation, supporting the use of venetoclax in this AML setting. The novel drug combinations here unveiled provide a rationale for evaluating these combinations in preclinical studies to accelerate the introduction of targeted therapies for the life-threatening KMT2A-AML subgroup of pediatric AML.

Pediatric acute myeloid leukemia – novel approaches

“…This study also noted excellent survival in patients able to reach transplant, with an estimated 12-month OS of 74.4%. This study also noted that patients with KMT2A rearrangements achieved a CR in 6/8 cases, consistent with preclinical evidence that venetoclax is active in this patient subset [15]. Finally, two reports of successful venetoclax therapy for NUP90::NSD1 fusion AML provide hope for this aggressive and challenging subset of AML [16,17].…”

Discovery of Small-Molecule TIM-3 Inhibitors for Acute Myeloid Leukemia Using Pharmacophore-Based Virtual Screening

“…Acute myeloid leukemia (AML) is a type of cancer that arises from stem cell precursors of the myeloid lineage. Unfortunately, AML has a poor prognosis, highlighting the urgent need for innovative and combined treatment approaches. − Immune evasion strategies employed by leukemia cells hinder T-cell-mediated immunity, leading to disease progression and relapse. − In this context, clinical trials evaluating monoclonal antibodies (mAbs) that target immune checkpoints have shown promising results for relapsed/refractory AML patients. − However, the administration of mAbs in AML patients required higher doses compared to solid tumor patients and was associated with potentially fatal immune-related adverse events (irAEs). , Moreover, mAbs have limitations such as limited tumor penetration, high production costs, and potential immunogenicity. − Additionally, mAbs generally have long half-lives, which can result in long-term on-target mediated irAEs. , In contrast, small molecules offer advantages as immune checkpoint inhibitors, including oral bioavailability and better tumor penetration. , They also provide flexibility in dosing regimens, which may help mitigate irAEs associated with mAbs. The introduction of small molecules as immune checkpoint inhibitors could greatly benefit combination therapies that target multiple receptors, enhancing the overall response rates of immunotherapy in AML.…”

Interactomics of CXXC proteins involved in epigenetic regulation of gene expression

“…[15]. Наибольший научный интерес к белкам СXXC7 и CXXC9 обусловлен тем, что они рассматриваются с точки зрения молекулярных мишеней для прототипов лекарств с целью фармакологической коррекции эпигенетических нарушений [16,17]. В зависимости от биологического контекста гены CXXC вносят разнонаправленный вклад в нормальные и патологические процессы, что можно проследить на следующих примерах из литературы.…”