Updates in KMT2A Gene Rearrangement in Pediatric Acute Lymphoblastic Leukemia

Abstract

The KMT2A (formerly MLL) encodes the histone lysine-specific N-methyltransferase 2A and is mapped on chromosome 11q23. KMT2A is a frequent target for recurrent translocations in acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or mixed lineage (biphenotypic) leukemia (MLL). Over 90 KMT2A fusion partners have been identified until now, including the most recurring ones—AFF1, MLLT1, and MLLT3—which encode proteins regulating epigenetic mechanisms. The presence of distinct KMT2A rearrangements is an independent dismal prognostic factor, while very few KMT2A rearrangements display either a good or intermediate outcome. KMT2A-rearranged (KMT2A-r) ALL affects more than 70% of new ALL diagnoses in infants (<1 year of age), 5–6% of pediatric cases, and 15% of adult cases. KMT2A-rearranged (KMT2A-r) ALL is characterized by hyperleukocytosis, a relatively high incidence of central nervous system (CNS) involvement, an aggressive course with early relapse, and early relapses resulting in poor prognosis. The exact pathways of fusions and the effects on the final phenotypic activity of the disease are still subjects of much research. Future trials could consider the inclusion of targeted immunotherapeutic agents and prioritize the identification of prognostic factors, allowing for the less intensive treatment of some infants with KMT2A ALL. The aim of this review is to summarize our knowledge and present current insight into the mechanisms of KMT2A-r ALL, portray their characteristics, discuss the clinical outcome along with risk stratification, and present novel therapeutic strategies.

Elucidating the Role of MLL1 nsSNPs: Structural and Functional Alterations and Their Contribution to Hematological Malignancies Susceptibility

“…A prior study reported an association between polymorphisms in both coding and non-coding regions of the MLL1 gene and leukemia [6]. However, this earlier study employed a limited number of in silico tools compared to the present study.…”

“…MLL1 primarily governs the initiation and elongation of transcription through epigenetic modifications within the promoter regions of target genes [5]. Additionally, the MLL1 protein plays a vital role in the regulation of hematopoietic cell proliferation and differentiation, along with the modulation of the Meis homeobox 1 (MEIS1) and homeobox A (HOXA) gene clusters [6]. When these genes experience irregular regulation, it disrupts proper hematopoietic development, frequently leading to the development of leukemia [7].…”

Impact of Histone Lysine Methyltransferase SUV4-20H2 on Cancer Onset and Progression with Therapeutic Potential

“…6.1. Targeting of KMT2A and DOT1L to Combat Different Forms of Myeloid Leukemia KMT2A also known as lysine methyltransferase 2A is responsible for the establishment of mono-and demethylation of H3K4 via a nonprogressive mechanism [72]. This epigenetic mark has gene-activating effects and is particularly important for early development and hematopoiesis [73,74].…”

Genomic Characterization of Partial Tandem Duplication Involving the KMT2A Gene in Adult Acute Myeloid Leukemia

“…These KMT2A gene rearrangements can occur in the context of fusion with other gene partners or result from partial tandem duplication within KMT2A (i.e., KMT2A-PTD). KMT2A fusions have been reported in 3% of primary pediatric and adult leukemia as well as 10% of secondary leukemia occurring following treatment with DNA topoisomerase II inhibitors [7][8][9][10][11][12][13]. KMT2A-PTDs are identified in 3-10% of AML cases, particularly in up to 25% of patients with a concurrent trisomy of chromosome 11 [1,4].…”