Firas El Chaer1, Michael Keng1, Karen K Ballen2. 1. Department of Medicine, Division of Hematology and Oncology, University of Virginia School of Medicine, 1215 Lee Street, Charlottesville, VA, 22903, USA. 2. Department of Medicine, Division of Hematology and Oncology, University of Virginia School of Medicine, 1215 Lee Street, Charlottesville, VA, 22903, USA. KB3TC@virginia.edu.
Abstract
PURPOSE OF REVIEW: Rearrangements of the histone lysine [K]-MethylTransferase 2A gene (KMT2A) gene on chromosome 11q23, formerly known as the mixed-lineage leukemia (MLL) gene, are found in 10% and 5% of adult and children ALL cases, respectively. The most common translocated genes are AFF1 (formerly AF4), MLLT3 (formerly AF9), and MLLT1 (formerly ENL). The bimodal incidence of MLL-r-ALL usually peaks in infants in their first 2 years of life and then declines thereafter during the pediatric/young adult phase until it increases again with age. MLL-rearranged ALL (MLL-r-ALL) is characterized by hyperleukocytosis, aggressive behavior with early relapse, relatively high incidence of central nervous system (CNS) involvement, and poor prognosis. RECENT FINDINGS: MLL-r-ALL cells are characterized by relative resistance to corticosteroids (due to Src kinase-induced phosphorylation of annexin A2) and L-asparaginase therapy, but they are sensitive to cytarabine chemotherapy (due to increased levels of hENT1 expression). Potential therapeutic targets include FLT3 inhibitors, MEK inhibitors, HDAC inhibitors, BCL-2 inhibitors, MCL-1 inhibitors, proteasome inhibitors, hypomethylating agents, Dot1L inhibitors, and CDK inhibitors. In this review, we discuss MLL-r-ALL focusing on clinical presentation, risk stratification, drug resistance, and treatment strategies, including potential novel therapeutic targets.
PURPOSE OF REVIEW: Rearrangements of the histone lysine [K]-MethylTransferase 2A gene (KMT2A) gene on chromosome 11q23, formerly known as the mixed-lineage leukemia (MLL) gene, are found in 10% and 5% of adult and children ALL cases, respectively. The most common translocated genes are AFF1 (formerly AF4), MLLT3 (formerly AF9), and MLLT1 (formerly ENL). The bimodal incidence of MLL-r-ALL usually peaks in infants in their first 2 years of life and then declines thereafter during the pediatric/young adult phase until it increases again with age. MLL-rearranged ALL (MLL-r-ALL) is characterized by hyperleukocytosis, aggressive behavior with early relapse, relatively high incidence of central nervous system (CNS) involvement, and poor prognosis. RECENT FINDINGS:MLL-r-ALL cells are characterized by relative resistance to corticosteroids (due to Src kinase-induced phosphorylation of annexin A2) and L-asparaginase therapy, but they are sensitive to cytarabine chemotherapy (due to increased levels of hENT1 expression). Potential therapeutic targets include FLT3 inhibitors, MEK inhibitors, HDAC inhibitors, BCL-2 inhibitors, MCL-1 inhibitors, proteasome inhibitors, hypomethylating agents, Dot1L inhibitors, and CDK inhibitors. In this review, we discuss MLL-r-ALL focusing on clinical presentation, risk stratification, drug resistance, and treatment strategies, including potential novel therapeutic targets.
Authors: Aidin Foroutan; Sadegheh Haghshenas; Pratibha Bhai; Michael A Levy; Jennifer Kerkhof; Haley McConkey; Marcello Niceta; Andrea Ciolfi; Lucia Pedace; Evelina Miele; David Genevieve; Solveig Heide; Mariëlle Alders; Giuseppe Zampino; Giuseppe Merla; Mélanie Fradin; Eric Bieth; Dominique Bonneau; Klaus Dieterich; Patricia Fergelot; Elise Schaefer; Laurence Faivre; Antonio Vitobello; Silvia Maitz; Rita Fischetto; Cristina Gervasini; Maria Piccione; Ingrid van de Laar; Marco Tartaglia; Bekim Sadikovic; Anne-Sophie Lebre Journal: Int J Mol Sci Date: 2022-02-05 Impact factor: 5.923
Authors: Janet Flores-Lujano; David Aldebarán Duarte-Rodríguez; Elva Jiménez-Hernández; Jorge Alfonso Martín-Trejo; Aldo Allende-López; José Gabriel Peñaloza-González; María Luisa Pérez-Saldivar; Aurora Medina-Sanson; José Refugio Torres-Nava; Karina Anastacia Solís-Labastida; Luz Victoria Flores-Villegas; Rosa Martha Espinosa-Elizondo; Raquel Amador-Sánchez; Martha Margarita Velázquez-Aviña; Laura Elizabeth Merino-Pasaye; Nora Nancy Núñez-Villegas; Ana Itamar González-Ávila; María de Los Ángeles Del Campo-Martínez; Martha Alvarado-Ibarra; Vilma Carolina Bekker-Méndez; Rocío Cárdenas-Cardos; Silvia Jiménez-Morales; Roberto Rivera-Luna; Haydee Rosas-Vargas; Norma C López-Santiago; Angélica Rangel-López; Alfredo Hidalgo-Miranda; Elizabeth Vega; Minerva Mata-Rocha; Omar Alejandro Sepúlveda-Robles; José Arellano-Galindo; Juan Carlos Núñez-Enríquez; Juan Manuel Mejía-Aranguré Journal: Front Public Health Date: 2022-09-14