MLL Leukemia and Future Treatment Strategies

Abstract

Chromosomal rearrangements of the MLL gene are associated with high-risk infant, pediatric, adult, and therapy-induced acute leukemias. So far, about 80 different direct MLL fusions and about 120 reciprocal MLL fusions have been characterized at the molecular level. The common theme in these leukemia-associated genetic rearrangements is the genetic disruption of the MLL gene. This leads to MLL-X fusion proteins that still bind to nuclear factors (e.g., MEN1, LEDGF), which in turn allow them to target promoters and cause ectopic gene transcription. In addition, the most frequent MLL fusions (MLL-AF4, MLL-AF9, MLL-AF10, and MLL-ENL) are all recruiting the wild-type AF4 multiprotein complex that contains the target proteins P-TEFb, BRD4, and DOT1L. Vice versa, reciprocal X-MLL fusions exhibit a PHD domain (H3K4me3 reader domain), sequester the histone acetyltransferases CREBBP and MOF1 and bear a histone methyltransferase domain at their very C-terminus (SET domain). Except for AF4-MLL, the functional consequences deriving from reciprocal fusion proteins are not very well understood. However, based on our knowledge about the above-mentioned MLL fusions, it is reasonable to inhibit their oncogenic activity in a targeted fashion. Recent efforts in developing such inhibitors and their mode of action will be critically discussed.

SET/MLL family proteins in hematopoiesis and leukemia

“…These differences may underlie the fact that only MLL1 is involved in chromosomal translocations in leukemia. The mechanisms by which MLL-fusion oncoproteins transform cells have been reviewed extensively [56][57][58][59], but the contribution of the non-translocated, wildtype allele remains controversial. Several early studies suggested that the remaining wild-type MLL1 molecule was required for maintaining MLL-AF9 initiated leukemia or that targeting the HMT activity of MLL1 would be therapeutically beneficial [60,61].…”

Six1 regulates leukemia stem cell maintenance in acute myeloid leukemia

“…The MLL gene encodes a H3K4 methyltransferase that is critical for development and hematopoiesis. Chromosomal rearrangements involving the MLL gene are associated with high‐risk infant, pediatric, adult and therapy‐induced acute leukemia . To date, over 79 different MLL fusions have been identified in acute leukemia patients .…”

“…Chromosomal rearrangements involving the MLL gene are associated with high-risk infant, pediatric, adult and therapyinduced acute leukemia. 4,5 To date, over 79 different MLL fusions have been identified in acute leukemia patients. 6 The most common MLL fusion partners include AF4, AF9, ENL, AF10 and ELL, which together account for over 80% of MLL-rearranged AML 7,8 and 4% of all AML patients.…”

Molecular characterization of KMT2A fusion partner genes in 13 cases of pediatric leukemia with complex or cryptic karyotypes

“…However, pediatric leukemias with rearrangements involving the promiscuous mixed‐lineage leukemia gene ( MLL ) continue to have a poor outcome. Hence, KMT2A rearrangements ( KMT2A ‐r) remain of great interest because of their wide variety, diverse biological effects, and clinical implications .…”