Novel Diagnostic and Therapeutic Options for KMT2A-Rearranged Acute Leukemias

Abstract

The <i>KMT2A</i> (<i>MLL</i>) gene rearrangements (<i>KMT2A</i>-r) are associated with a diverse spectrum of acute leukemias. Although most <i>KMT2A</i>-r are restricted to nine partner genes, we have recently revealed that <i>KMT2A</i>-<i>USP2</i> fusions are often missed during FISH screening of these genetic alterations. Therefore, complementary methods are important for appropriate detection of any <i>KMT2A</i>-r. Here we use a machine learning model to unravel the most appropriate markers for prediction of <i>KMT2A</i>-r in various types of acute leukemia. A Random Forest and LightGBM classifier was trained to predict <i>KMT2A</i>-r in patients with acute leukemia. Our results revealed a set of 20 genes capable of accurately estimating <i>KMT2A</i>-r. The <i>SKIDA1</i> (AUC: 0.839; CI: 0.799-0.879) and <i>LAMP5</i> (AUC: 0.746; CI: 0.685-0.806) overexpression were the better markers associated with <i>KMT2A</i>-r compared to <i>CSPG4</i> (also named <i>NG2</i>; AUC: 0.722; CI: 0.659-0.784), regardless of the type of acute leukemia. Of importance, high expression levels of <i>LAMP5</i> estimated the occurrence of all <i>KMT2A-USP2</i> 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 <i>KMT2A</i>-r leukemia. We observed that <i>KMT2A</i>-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 <i>ex-vivo</i> drug sensitivity to small-molecule inhibitors reveals that Foretinib is a promising drug option for AML patients carrying <i>FLT3</i> activating mutations. Thus, we provide novel and accurate options for the diagnostic screening and therapy of <i>KMT2A</i>-r leukemia, regardless of leukemia subtype.