Low-level expression of SAMHD1 in acute myeloid leukemia (AML) blasts correlates with improved outcome upon consolidation chemotherapy with high-dose cytarabine-based regimens

George Z Rassidakis,George Z Rassidakis,L Jeffrey Medeiros,Hagop M Kantarjian,Siok-Bian Ng,Jan-Inge Henter,Ioanna Xagoraris,Joseph D Khoury,Torsten Schaller,Chin Hin Ng,Nikolas Herold,Nikolas Herold,Jan-Inge Henter,Nikolaos Tsesmetzis,Wee Joo Chng,Ida Hed Myrberg,Ida Hed Myrberg,Michael Andreeff,Sean G Rudd,Sean G Rudd,Benedict Yan,Torsten Schaller,Nikolaos Tsesmetzis,Farhad Ravandi,Benedict Yan

doi:10.1038/s41408-018-0134-z

Abstract

Sterile alpha motif and histidine/aspartic acid domain containing protein 1 (SAMHD1) limits the efficacy of cytarabine (ara-C) used in AML by hydrolyzing its active metabolite ara-CTP and thus represents a promising therapeutic target. SAMHD1 has also been implicated in DNA damage repair that may impact DNA damage-inducing therapies such as anthracyclines, during induction therapy. To determine whether SAMHD1 limits ara-C efficacy during induction or consolidation therapy, SAMHD1 protein levels were assessed in two patient cohorts of de novo AML from The University of Texas MD Anderson Cancer Center (USA) and the National University Hospital (Singapore), respectively, using immunohistochemistry and tissue microarrays. SAMHD1 was expressed at a variable level by AML blasts but not in a broad range of normal hematopoietic cells in reactive bone marrows. A sizeable patient subset with low SAMHD1 expression (<25% of positive blasts) was identified, which was significantly associated with longer event-free (EFS) and overall (OS) survival in patients receiving high-dose cytarabine (HDAC) during consolidation. Therefore, evaluation of SAMHD1 expression level in AML blasts at diagnosis, may stratify patient groups for future clinical trials combining HDAC with novel SAMHD1 inhibitors as consolidation therapy.

Highlights

Acute myeloid leukemia (AML) is a heterogeneous group of neoplasms derived from myeloid progenitor cells
In reactive bone marrows, double immunohistochemistry demonstrated that normal hematopoietic stem cells and progenitors (CD34+), cells belonging to the myeloid/erythroid lineage (MPO+ or GPA+) as well as megakaryocytes (CD61+) were all negative for SAMHD1 expression (Fig. 1)
Here, we report for the first time the expression patterns of SAMHD1 in normal bone marrows using an optimized double immunohistochemistry assay that analysed SAMHD1 expression in normal hematopoietic cells of all three lineages including normal CD34+ cells

Summary

Introduction

Acute myeloid leukemia (AML) is a heterogeneous group of neoplasms derived from myeloid progenitor cells. The most important drugs in the treatment of AML patients are anthracyclines that contribute heavily to the success of remission induction therapy[3] and cytarabine (ara-C). The inter-patient variability of response to high-dose ara-C (HDAC) regimens correlates. Rassidakis et al Blood Cancer Journal (2018)8:98 with the propensity of AML blasts to accumulate ara-CTP intracellularly[5], the main determinant of ara-C efficacy[6]. SAMHD1 decreases intracellular ara-CTP concentrations, limiting its lethal mis-incorporation into DNA and promoting cell survival[7,13]. Ara-C treatment was more effective in AML xenotransplant mouse models lacking functional SAMHD1 as compared to SAMHD1-proficient counterparts[7,8,11]. Depletion of SAMHD1 in primary AML blasts using the lentiviral protein X (Vpx), which targets SAMHD1 for degradation, increased ara-C sensitivity[7]

Methods

Results

Conclusion