Novel Diagnostic and Therapeutic Options for KMT2A-Rearranged Acute Leukemias

Abstract

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.

Loss of VHL-mediated pRb regulation promotes clear cell renal cell carcinoma

“…It was found to be differentially expressed in the regulatory T cells of Autoimmune polyendocrine syndrome type I (APS-1) patients compared to healthy patients 102 . SKIDA1 was also described as the best predictor of KMT2A (Mixed-lineage-leukemia) gene rearrangements 103 . Its role however, in tumor development has not been defined.…”

Inducible MLL-AF9 Expression Drives an AML Program during Human Pluripotent Stem Cell-Derived Hematopoietic Differentiation

“…Indeed, typical gene expression profiles that have well-described roles in both the induction and maintenance of MLL-AF9 AML were enriched following MLL-AF9 activation (e.g., MEIS1 , HOXA9 , HOXA10 , CDK6 , ZNF521 ) [ 26 , 27 , 28 , 29 , 43 ]. Moreover, we identified MLL-AF9-associated core genes that are faithfully represented in primary MLL-AF9 AML, including known targets such as HOXA10 , CDK6 , and ZNF521 , as well as targets that have a presently unknown role in MLL-AF9 AML, e.g., SKIDA1 , which seems to be a promising predictor of MLL-rearranged AML [ 45 ]. This indicates that we have uncovered a repertoire of gene profiles that includes factors important for leukemic transformation and maintenance in MLL-AF9 AML.…”

Inducible MLL-AF9 expression drives an AML program during human pluripotent stem cell-derived hematopoietic differentiation

“…Among the core genes are well known MLL-AF9-associated genes (HOXA10 and ZNF521) and genes that have a thus far unknown role in the context of MLL-AF9 during early hematopoiesis (14,33). For example SKIDA1, which seems to be a promising predictor of MLL-rearranged AML (39). Additionally, by integrating transcriptomics with accessible epigenetic regions, we were able to predict and rank key TFs in MLL-AF9-mediated gene regulation.…”