Evidence map›Paper›PMID 35153769›Full record

ArticleFrontiers in pharmacology2021

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

Claudia Tregnago, Maddalena Benetton, Ambra Da Ros, Giulia Borella, Giorgia Longo, Katia Polato, Samuela Francescato, Alessandra Biffi, Martina Pigazzi

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Frontiers in pharmacology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.

0numbers the graph read from it
0cells of the map it votes in
7citing papers in PubMed
0.8field-weighted citation impact, top 32% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

7 citing papers in PubMed, 10 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

9 authors at 1 institution in 1 country.

Claudia TregnagoPediatric Haematology-Oncology and Hematopoietic Cell and Gene Therapy Division, Woman and Child Health Department, University-Hospital of Padova, Padova, Italy.
Maddalena BenettonPediatric Haematology-Oncology and Hematopoietic Cell and Gene Therapy Division, Woman and Child Health Department, University-Hospital of Padova, Padova, Italy.
Ambra Da RosPediatric Haematology-Oncology and Hematopoietic Cell and Gene Therapy Division, Woman and Child Health Department, University-Hospital of Padova, Padova, Italy.
Giulia BorellaPediatric Haematology-Oncology and Hematopoietic Cell and Gene Therapy Division, Woman and Child Health Department, University-Hospital of Padova, Padova, Italy.
Giorgia LongoPediatric Haematology-Oncology and Hematopoietic Cell and Gene Therapy Division, Woman and Child Health Department, University-Hospital of Padova, Padova, Italy.
Katia PolatoPediatric Haematology-Oncology and Hematopoietic Cell and Gene Therapy Division, Woman and Child Health Department, University-Hospital of Padova, Padova, Italy.
Samuela FrancescatoPediatric Haematology-Oncology and Hematopoietic Cell and Gene Therapy Division, Woman and Child Health Department, University-Hospital of Padova, Padova, Italy.
Alessandra BiffiPediatric Haematology-Oncology and Hematopoietic Cell and Gene Therapy Division, Woman and Child Health Department, University-Hospital of Padova, Padova, Italy.
Martina PigazziPediatric Haematology-Oncology and Hematopoietic Cell and Gene Therapy Division, Woman and Child Health Department, University-Hospital of Padova, Padova, Italy.
University of Padua · IT

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

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

Indexed as

AMLKMT2Asynergytargeted drugsvenetoclax

Identifiers

PMID35153769
PMCPMC8830338
OpenAlexW4210794807

What OpenQuestion holds

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LicenceCC BY
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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.