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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Main Authors: Bruno A. Lopes (Author), Caroline Pires Poubel (Author), Cristiane Esteves Teixeira (Author), Aurélie Caye-Eude (Author), Hélène Cavé (Author), Claus Meyer (Author), Rolf Marschalek (Author), Mariana Boroni (Author), Mariana Emerenciano (Author)
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Published: Frontiers Media S.A., 2022-06-01T00:00:00Z.
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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.