Novel Diagnostic and Therapeutic Options for KMT2A-Rearranged Acute Leukemias
The KMT2A (MLL) gene rearrangements (KMT2A-r) are associated with a diverse spectrum of acute leukemias. Although most KMT2A-r are restricted to nine partner genes, we have recently revealed that KMT2A-USP2 fusions are often missed during FISH screening of these genetic alterations. Therefore, compl...
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Frontiers Media S.A.,
2022-06-01T00:00:00Z.
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LEADER | 00000 am a22000003u 4500 | ||
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001 | doaj_6598dfb31ad047d2baac2bc909938f13 | ||
042 | |a dc | ||
100 | 1 | 0 | |a Bruno A. Lopes |e author |
700 | 1 | 0 | |a Caroline Pires Poubel |e author |
700 | 1 | 0 | |a Caroline Pires Poubel |e author |
700 | 1 | 0 | |a Cristiane Esteves Teixeira |e author |
700 | 1 | 0 | |a Aurélie Caye-Eude |e author |
700 | 1 | 0 | |a Aurélie Caye-Eude |e author |
700 | 1 | 0 | |a Hélène Cavé |e author |
700 | 1 | 0 | |a Hélène Cavé |e author |
700 | 1 | 0 | |a Claus Meyer |e author |
700 | 1 | 0 | |a Rolf Marschalek |e author |
700 | 1 | 0 | |a Mariana Boroni |e author |
700 | 1 | 0 | |a Mariana Emerenciano |e author |
245 | 0 | 0 | |a Novel Diagnostic and Therapeutic Options for KMT2A-Rearranged Acute Leukemias |
260 | |b Frontiers Media S.A., |c 2022-06-01T00:00:00Z. | ||
500 | |a 1663-9812 | ||
500 | |a 10.3389/fphar.2022.749472 | ||
520 | |a The KMT2A (MLL) gene rearrangements (KMT2A-r) are associated with a diverse spectrum of acute leukemias. Although most KMT2A-r are restricted to nine partner genes, we have recently revealed that KMT2A-USP2 fusions are often missed during FISH screening of these genetic alterations. Therefore, complementary methods are important for appropriate detection of any KMT2A-r. Here we use a machine learning model to unravel the most appropriate markers for prediction of KMT2A-r in various types of acute leukemia. A Random Forest and LightGBM classifier was trained to predict KMT2A-r in patients with acute leukemia. Our results revealed a set of 20 genes capable of accurately estimating KMT2A-r. The SKIDA1 (AUC: 0.839; CI: 0.799-0.879) and LAMP5 (AUC: 0.746; CI: 0.685-0.806) overexpression were the better markers associated with KMT2A-r compared to CSPG4 (also named NG2; AUC: 0.722; CI: 0.659-0.784), regardless of the type of acute leukemia. Of importance, high expression levels of LAMP5 estimated the occurrence of all KMT2A-USP2 fusions. Also, we performed drug sensitivity analysis using IC50 data from 345 drugs available in the GDSC database to identify which ones could be used to treat KMT2A-r leukemia. We observed that KMT2A-r cell lines were more sensitive to 5-Fluorouracil (5FU), Gemcitabine (both antimetabolite chemotherapy drugs), WHI-P97 (JAK-3 inhibitor), Foretinib (MET/VEGFR inhibitor), SNX-2112 (Hsp90 inhibitor), AZD6482 (PI3Kβ inhibitor), KU-60019 (ATM kinase inhibitor), and Pevonedistat (NEDD8-activating enzyme (NAE) inhibitor). Moreover, IC50 data from analyses of ex-vivo drug sensitivity to small-molecule inhibitors reveals that Foretinib is a promising drug option for AML patients carrying FLT3 activating mutations. Thus, we provide novel and accurate options for the diagnostic screening and therapy of KMT2A-r leukemia, regardless of leukemia subtype. | ||
546 | |a EN | ||
690 | |a KMT2A | ||
690 | |a MLL | ||
690 | |a acute leukemia | ||
690 | |a biomarker | ||
690 | |a machine learning | ||
690 | |a therapy | ||
690 | |a Therapeutics. Pharmacology | ||
690 | |a RM1-950 | ||
655 | 7 | |a article |2 local | |
786 | 0 | |n Frontiers in Pharmacology, Vol 13 (2022) | |
787 | 0 | |n https://www.frontiersin.org/articles/10.3389/fphar.2022.749472/full | |
787 | 0 | |n https://doaj.org/toc/1663-9812 | |
856 | 4 | 1 | |u https://doaj.org/article/6598dfb31ad047d2baac2bc909938f13 |z Connect to this object online. |