Perturbation of Methionine/S-adenosylmethionine Metabolism as a Novel Vulnerability in MLL Rearranged Leukemia.

Barve Barve,Vega Vega,Wunderlich Wunderlich,Shah Shah,Siskind Siskind,Casson Casson,Beverly Beverly,Ghare Ghare

doi:10.3390/cells8111322

Abstract

Leukemias bearing mixed lineage leukemia (MLL) rearrangement (MLL-R) resulting in expression of oncogenic MLL fusion proteins (MLL-FPs) represent an especially aggressive disease subtype with the worst overall prognoses and chemotherapeutic response. MLL-R leukemias are uniquely dependent on the epigenetic function of the H3K79 methyltransferase DOT1L, which is misdirected by MLL-FPs activating gene expression, driving transformation and leukemogenesis. Given the functional necessity of these leukemias to maintain adequate methylation potential allowing aberrant activating histone methylation to proceed, driving leukemic gene expression, we investigated perturbation of methionine (Met)/S-adenosylmethionine (SAM) metabolism as a novel therapeutic paradigm for MLL-R leukemia. Disruption of Met/SAM metabolism, by either methionine deprivation or pharmacologic inhibition of downstream metabolism, reduced overall cellular methylation potential, reduced relative cell numbers, and induced apoptosis selectively in established MLL-AF4 cell lines or MLL-AF6-expressing patient blasts but not in BCR-ABL-driven K562 cells. Global histone methylation dynamics were altered, with a profound loss of requisite H3K79 methylation, indicating inhibition of DOT1L function. Relative occupancy of the repressive H3K27me3 modification was increased at the DOT1L promoter in MLL-R cells, and DOT1L mRNA and protein expression was reduced. Finally, pharmacologic inhibition of Met/SAM metabolism significantly prolonged survival in an advanced, clinically relevant patient–derived MLL-R leukemia xenograft model, in combination with cytotoxic induction chemotherapy. Our findings provide support for further investigation into the development of highly specific allosteric inhibitors of enzymatic mediators of Met/SAM metabolism or dietary manipulation of methionine levels. Such inhibitors may lead to enhanced treatment outcomes for MLL-R leukemia, along with cytotoxic chemotherapy or DOT1L inhibitors.

Highlights

Mixed lineage leukemia 1 (MLL) gene rearrangement is a defining feature of a unique group of aggressive and chemotherapy resistant acute leukemias
While modern induction chemotherapy and hematopoietic stem cell transplantation (HSCT) have dramatically improved overall leukemia survival rates, patients diagnosed with MLL-R leukemia have a poor prognosis, with an overall survival less than 50%, and this prognosis is not improved by allogenic HSCT [3]
MLL-R is detected in 10% of all cases of leukemia and 80% of all pediatric leukemias, highlighting the need for novel, highly efficacious therapeutic paradigms for MLL-R leukemia

Summary

Introduction

Mixed lineage leukemia 1 (MLL) gene rearrangement is a defining feature of a unique group of aggressive and chemotherapy resistant acute leukemias. Rearrangement of the MLL gene results in fusion to a variety of partner genes, with approximately 80% occurring with one of six common gene partners (see below). MLL-R causes the aberrant expression of oncogenic MLL fusion proteins (MLL-FPs), and disease typically manifests as either acute myeloid or acute lymphoid leukemias (AML or ALL) and accounts for 10% of adult AML cases and 70–80% of infant leukemias [2]. While modern induction chemotherapy and hematopoietic stem cell transplantation (HSCT) have dramatically improved overall leukemia survival rates, patients diagnosed with MLL-R leukemia have a poor prognosis, with an overall survival less than 50%, and this prognosis is not improved by allogenic HSCT [3]. Novel treatment paradigms must be investigated for MLL-R leukemias, alone and in combination with standard of care (SOC) cytotoxic induction chemotherapeutics

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Results

Conclusion