Genomic analysis in myeloid sarcoma and comparison with paired acute myeloid leukemia

Summary

Myeloid sarcoma (MS) is a rare manifestation of acute myeloid leukemia (AML) characterized by extramedullary proliferation of myeloid blasts. Owing to the rarity of MS, the clonal evolution of cell populations giving rise to MS is not well understood. To study the genomic signature of MS, we used a capture-based next-generation sequencing panel targeting 479 cancer genes to interrogate the genetic variants present in MS samples and compared their genetic profiles with their paired AML samples from a cohort of seven individuals. We identified a spectrum of single-nucleotide variants (SNVs) and a spectrum of copy number alterations in MS. Our study found that variant profiles observed in MS were generally similar to AML from the same individual, supporting the notion that these tumors are derived from a common precursor, rather than de novo tumors in a susceptible host. In addition, MS cases with a higher number of SNVs show worse clinical outcomes than MS with a lower number of SNVs. Identification of these abnormalities could potentially contribute to improved prognostic classification and identify new therapeutic targets for MS.

Introduction

Myeloid sarcoma (MS), also termed granulocytic sarcoma or chloroma [1], is a rare extramedullary tumor consisting of proliferation of myeloblasts, with or without maturation [2]. MS can occur in any organ, but occurs most commonly in the skin, gastrointestinal tract, lymph nodes, and bone [3]. The clinical history of patients with MS is variable, with MS occurring either in isolation, or concurrently with acute myeloid leukemia (AML), or as extramedullary relapse of AML [1,4]. MS can also develop concomitantly with other myeloid neoplasms such as myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), and myelodysplastic/myeloproliferative neoplasm [2].

There are only limited studies on the cytogenetic and molecular features of MS. Fluorescence in situ hybridization (FISH) analysis of MS cases has shown clonal abnormalities including monosomy 7, trisomy 8, t(8; 21) [5], and KMT2A (MLL) gene rearrangement [6,7]. Comparative genomic hybridization of MS cases has shown chromosome 8 abnormalities, loss of 4q, 6q, and 12p, gain of 11q, 13q, 19, and 21 [2,8], and isochromosome 17q [2]. One next-generation sequencing (NGS) study [3] of 21 AML-associated genes using DNA from six MS cases showed genetic overlap between AML and MS, with mutations found in the tyrosine kinases FLT3 and KIT, the WT1 tumor suppressor gene, the epigenetic regulators TET1, ASXL1, and EZH2, and the RNA spliceosome protein SF3B1. However, the prognostic and therapeutic implications of cytogenetic and molecular abnormalities in MS are not as well studied as in AML.

The prognosis of MS has not been well understood in part owing to the rarity of this disorder. MS is generally associated with a poor outcome [[9], [10], [11]], but in other studies, isolated MS may demonstrate better survival outcomes than AML [12]. Given the distinct biologic behavior of MS compared with conventional AML, we hypothesized that MS may demonstrate a genetic profile different from conventional AML. Identification of these abnormalities could potentially improve prognostic classification and identify new therapeutic targets for this rare aggressive tumor.