Myeloid cell leukemia-1 dependence in acute myeloid leukemia: a novel approach to patient therapy.

Tapan Mahendra Kadia,Marina Konopleva,Hagop M Kantarjian

doi:10.18632/oncotarget.26579

Tapan Mahendra Kadia, Marina Konopleva + Show 1 more

Open Access

https://doi.org/10.18632/oncotarget.26579

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Abstract

Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults, affecting approximately 21,000 people annually (nearly 11,000 deaths) in the United States. B-cell lymphoma 2 (BCL-2) family proteins, notably myeloid cell leukemia-1 (MCL-1), have been associated with both the development and persistence of AML. MCL-1 is one of the predominant BCL-2 family members expressed in samples from patients with untreated AML. MCL-1 is a critical cell survival factor for cancer and contributes to chemotherapy resistance by directly affecting cell death pathways. Here, we review the role of MCL-1 in AML and the mechanisms by which the potent cyclin-dependent kinase 9 inhibitor alvocidib, through regulation of MCL-1, may serve as a rational therapeutic approach against the disease.

Highlights

Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults
These findings provide key information on how the diverse functions of myeloid cell leukemia (MCL)-1 may contribute to cell homeostasis and function, supporting the evidence that high levels of myeloid cell leukemia-1 (MCL-1) in human cancers contribute to malignant cell growth and evasion of apoptosis [165]
Approaches to down-regulate MCL-1 expression have been directed multiple ways: inhibiting its transcription via CDK9 inhibition, as is the case with alvocidib and other cyclindependent kinase (CDK) inhibitors [113, 114]; at the translational level, as occurring in human leukemia cells exposed to sorafenib [171]; or by targeting protein-protein www.oncotarget.com interactions to directly affect MCL-1 anti-apoptotic activity [8, 172,173,174]

Summary

INTRODUCTION

Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults. According to the American Cancer Society, the incidence of AML has increased 1.7% per year from 2004 to 2013 [1]. In addition to its role in controlling and opposing cell death, which is related to its localization on the outer mitochondrial membrane, an amino-terminally truncated isoform of MCL-1 was found to be imported into the mitochondrial matrix where it facilitates normal mitochondrial function, membrane potential, ATP production, respiration, cristae ultrastructure, and maintenance of oligomeric ATP synthase [164] These findings provide key information on how the diverse functions of MCL-1 may contribute to cell homeostasis and function, supporting the evidence that high levels of MCL-1 in human cancers contribute to malignant cell growth and evasion of apoptosis [165]. Approaches to down-regulate MCL-1 expression have been directed multiple ways: inhibiting its transcription via CDK9 inhibition, as is the case with alvocidib and other CDK inhibitors [113, 114]; at the translational level, as occurring in human leukemia cells exposed to sorafenib [171]; or by targeting protein-protein www.oncotarget.com interactions to directly affect MCL-1 anti-apoptotic activity [8, 172,173,174]. Given the marked interest in MCL-1 inhibitors and the efforts currently underway in academic institutions and pharmaceutical laboratories, a summary of some of these studies has been recently published [172]

SUMMARY

Findings

CONFLICTS OF INTEREST