Molecular mechanisms of MLL-associated leukemia

Abstract

genes [1][2][3]. To date, more than 70 MLL fusion genes have been reported [4]. Leukemia associated with MLL gene alterations (hereafter referred to as MLL-associated leukemia) accounts for ~5-10 % of total acute leukemia cases and is a major cause of infant acute lymphoblastic leukemia [5]. Clinical outcomes of MLL-associated leukemia are often unfavorable; therefore, the development of better therapeutic strategies is needed.Significant progress in understanding MLL-associated leukemia has been achieved in the past two decades. The coding sequence of the MLL gene was established in the early 1990s [1,2]. The first mouse model of MLL-associated leukemia using retroviral gene transduction or knockin strategies was generated in the late 1990s [6,7], and several other sophisticated disease models using murine cells [8][9][10][11][12] and human cells [13,14] that mimic the human disease have been developed. Recent technological advances in genetics, such as DNA microarray and short hairpin RNA library screening have enabled identification of a number of novel pathways that play critical roles in the development of MLL-associated leukemia, and these are reviewed in detail elsewhere [15]. In this review, I focus on the mechanistic aspects of MLL fusion-dependent leukemic transformation. MLL activates transcription of cellular memory genesMLL is structurally similar to the Drosophila trithorax protein, as both have an evolutionarily conserved SET domain (Fig. 1a) [1, 2]. Knockout of Mll results in a loss of the expression of several posterior homeobox (Hox) genes [16,17], similar to the consequences of the genetic ablation of trithorax in Drosophila [18,19]. Hox genes are Abstract Gene rearrangements of the mixed lineage leukemia (MLL) gene cause aggressive leukemia. The fusion of MLL and its partner genes generates various MLL fusion genes, and their gene products trigger aberrant self-renewal of hematopoietic progenitors leading to leukemia. Since the identification of the MLL gene two decades ago, a substantial amount of information has been obtained regarding the mechanisms by which MLL mutations cause leukemia. Wild-type MLL maintains the expression of Homeobox (HOX) genes during development. MLL activates the expression of posterior HOX-A genes in the hematopoietic lineage to stimulate the expansion of immature progenitors. MLL fusion proteins constitutively activate the HOX genes, causing aberrant self-renewal. The modes of transcriptional activation vary depending on the fusion partners and can be categorized into at least four groups. Here I review the recent progress in research related to the molecular mechanisms of MLL fusion-dependent leukemogenesis.

Epigenetics in normal and malignant hematopoiesis: An overview and update 2017

“…Kmt2a regulates multiple HSC genes, including Hoxa9, Meis1, Mecom and Prdm16 . Several models for KMT2A ‐rearranged leukemia have been developed using retroviral transduction and mouse knockin strategies . Retrovirus‐mediated transduction of KMT2A‐fusion proteins, such as KMT2A (MLL)‐AF9 and KMT2A‐ENL, can transform not only HSC but also myeloid progenitors to produce AML in vivo .…”

Relatively favorable prognosis for MLL‐rearranged childhood acute leukemia with reciprocal translocations

“…Mixed‐lineage leukemia ( MLL )‐related structural abnormalities are one of the major pre‐leukemic events linked to unfavorable prognosis in children with acute leukemia (AL) . MLL‐rearranged (MLL‐r) leukemia is a recognized aggressive hematopoietic malignancy that causes abnormal self‐renewal of hematopoietic progenitors and the derangement of epigenetic regulation . MLL rearrangements account for 15–20% of pediatric acute myeloid leukemia (AML) cases, 2.5–5% of childhood acute lymphoblastic leukemia (ALL) cases, and over 70% of infant leukemia cases.…”

First case of B ALL with KMT2A-MAML2 rearrangement: a case report

“…Translocation of the KMT2A gene, better known as the MLL gene, is present in 7–10% of B acute lymphoblastic leukemias, AFF1 (or AF4 ) being the most frequent partner gene. The prognosis of B acute lymphoblastic leukemias (B ALL) with KMT2A gene translocations are usually poor, especially with KMT2A-AFF1 fusions [1, 2]. One of its rare partner genes, mastermind like 2 ( MAML2 ) gene has been reported in four cases of myeloid neoplasms after chemotherapies: two cases of acute myeloid leukemia (AML) and two cases of myelodysplasic syndromes (MDS) [3].…”