Genetic Alterations in Essential Thrombocythemia Progression to Acute Myeloid Leukemia: A Case Series and Review of the Literature

Abstract

The genetic events associated with transformation of myeloproliferative neoplasms (MPNs) to secondary acute myeloid leukemia (sAML), particularly in the subgroup of essential thrombocythemia (ET) patients, remain incompletely understood. Deep studies using high-throughput methods might lead to a better understanding of genetic landscape of ET patients who transformed to sAML. We performed array-based comparative genomic hybridization (aCGH) and whole exome sequencing (WES) to analyze paired samples from ET and sAML phases. We investigated five patients with previous history of MPN, which four had initial diagnosis of ET (one case harboring JAK2 p.Val617Phe and the remaining three CALR type II p.Lys385fs*47), and one was diagnosed with MPN/myelodysplastic syndrome with thrombocytosis (SF3B1 p.Lys700Glu). All were homogeneously treated with hydroxyurea, but subsequently transformed to sAML (mean time of 6 years/median of 4 years to transformation). Two of them have chromosomal abnormalities, and both acquire 2p gain and 5q deletion at sAML stage. The molecular mechanisms associated with leukemic progression in MPN patients are not clear. Our WES data showed TP53 alterations recurrently observed as mutations (missense and frameshift) and monoallelic loss. On the other hand, aCGH showed novel chromosome abnormalities (+2p and del5q) potentially associated with disease progression. The results reported here add valuable information to the still fragmented molecular basis of ET to sAML evolution. Further studies are necessary to identify minimal deleted/amplified region and genes relevant to sAML transformation.

Keywords: +2p; array-based comparative genomic hybridization; essential thrombocythemia; myeloproliferative neoplasms; secondary acute myeloid leukemia; whole exome sequencing.

Figure 1

Longitudinal analysis of uniformly treated MPN cases. Five cases were analyzed by aCGH and WES before and after therapy. The horizontal axis represents the timeline (in years) of sample collection. Each case is presented in the right legend. Squares are showing samples analyzed only by aCGH and circles by the two methodologies applied. aCGH, array-based comparative genomic hybridization; MPN, myeloproliferative neoplasm; WES, whole exome sequencing.

Figure 2

(A,B) Size and type of the abnormalities found at chronic phase (A) and sAML (B) samples from three patients analyzed by aCGH. Abnormalities found at chronic phase remained until sAML. Gains are represented above and losses below X-axis; note that there are more abnormalities found at sAML, and they are larger compared to chronic phase. aCGH, array-based comparative genomic hybridization; chr, chromosome; MPN, myeloproliferative neoplasms; sAML, secondary acute myeloid leukemia.

Figure 3

(A–C) Genomic landscape of thrombocythosis (ET and MPN/MDS) that progressed to sAML. VAF of candidate driver mutations or paralogous genes already associated with MPN phenotype in each patient analyzed are depicted in upper panels. Model of clonal evolution of MPN to sAML showing average VAF of each subclone in the stages analyzed. Clonal evolution complexity showing VAF of mutations found in each clone per patient in MPN (abcissa) and sAML (ordinate) stages is depicted in the lower panels. VAF plots were generated by mclust after running fpc and nselectboot functions. ET, essential thrombocythemia; MDS, myelodysplastic syndrome; MPN, myeloproliferative neoplasm; sAML, secondary acute myeloid leukemia.; UPN, unique patient number; VAFs, variant allele frequencies.