MLL leukemia and future treatment strategies

Archiv der Pharmazie
Rolf Marschalek

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. Re...Continue Reading

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Citations

Feb 10, 2016·Leukemia·U DuffnerP Kidd
Nov 1, 2016·International Journal of Hematology·Weiwei Yang, Patricia Ernst
May 6, 2019·Cancer Science·Yajing ChuWeiping Yuan
Aug 10, 2019·Genes & Development·Christian HurtzMarkus Müschen
Jul 14, 2018·BioMed Research International·Jiaqi TanJianfeng Zhou
Jun 30, 2019·Journal of Hematology & Oncology·Krzysztof BrzezinkaCarlo Stresemann
Apr 30, 2020·Biochimica Et Biophysica Acta. Gene Regulatory Mechanisms·Subham BasuDebabrata Biswas
Oct 11, 2020·EBioMedicine·Gisela Jimenez-DuranSeth L Masters

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