Acquisition of Receptor Tyrosine Kinases, JAK2, or Ras Pathway Mutations Is Associated with Acute Myeloid Leukemia Transformation In Patients with Myelodysplastic Syndrome
Authors: Lin Tung-Liang , Kuo Ming-Chung , Liang Der-Cherng , Huang Chein-Fuang , Lin Tung-Huei , Lee En-Hui , Shih Yu-Shu , Wu Jin-Hou , Shih Lee-Yung 
Published: October 2019

Abstract
Abstract 4025

Background.
Myelodysplastic syndrome (MDS) is a heterogeneous disease group characterized by ineffective hematopoiesis, cytopenias, and various probability of acute myeloid leukemia (sAML) transformation. The molecular genetic changes from MDS to sAML are not clear. We aimed to determine the roles of gene mutations involving receptor tyrosine kinases (RTKs: FLT3/ITD, FLT3/TKD, c-KIT, or c-FMS), Ras pathways (NRAS, KRAS, or PTPN11) and JAK2V617F in the progression of MDS by analyzing matched paired high risk MDS and sAML samples.

Patients and Methods.
A total of 122 patients (50 RAEB1, 52 RAEB2, and 20 RCMD) were examined; 82 had sAML evolution and 68 of them had matched paired bone marrow samples (22 RAEB1, 29 RAEB2 and 17 RCMD) available for comparative analysis for at least one gene mutation. Mutational analyses were performed by DNA/cDNA PCR with GeneScan analysis for FLT3/ITD, PCR-RFLP followed by direct sequencing for FLT3/TKD, DNA/cDNA PCR and direct sequencing for c-KIT, c-FMS, NRAS, KRAS, and PTPN11 mutations, and allele-specific PCR for JAK2V617F mutation.

Results.
Of the 122 cases, 3 had FLT3 mutations (2 FLT3/ITD, 1 FLT3/TKD), none had c-KIT or KRAS mutations, one had c-FMS mutation, 3 each had JAK2V617F and NRAS mutations, and 2 had PTPN11 mutations. Patients harboring mutations of RTK or Ras pathways at diagnosis were not at increased risk of sAML (P=0.5501 and 1.0000, respectively). Presence of any RTK mutations at diagnosis (N=3) did not influence outcome in terms of time to sAML (P=0.6711) or overall survival (OS) (P=0.7162) compared to those who did not have any RTK mutation (N=119). Time to sAML (P=0.6093) or OS (P=0.4515) were not different between patients carrying Ras pathway mutations (N=5) and those without any mutations (N=117).
The results of the mutation status for each gene in the 68 paired samples are shown in Table 1. Seven patients (10.3%) gained mutations of RTK pathways at sAML. Patients with mutations of RTKs at diagnosis had shorter time to sAML than those who did not have any mutations (3.4±2.0 vs 10.9±1.1 months, P=0.0004), but the OS was not different between these two groups (P=0.2015). For the Ras pathways, 12 patients (17.6%) acquired mutations at sAML, one of them also acquired FLT3/TKD mutation. Additional one patient gained JAK2V617F mutation. Time to sAML (P=0.2578) and OS (P=0.2637) were not different between patients with Ras pathway mutations at diagnosis and those without mutations. Taken together, 8 patients (11.8%) had mutations at diagnosis and 24 (35.3%) at sAML, one lost PTPN11 mutation and 19 patients (27.9%) acquired mutations which drive proliferation and survival of malignant clone during the progression to sAML from MDS.

Conclusions.
Our results showed that acquisition of mutations involving RTK, JAK2, or Ras pathways played important roles in the progression of MDS to sAML. Patients with mutations of RTKs progressed to sAML more rapidly.
Supported by grants NHRI-EX99-9711SI, NSC97-2314-B-182-011-MY3 and DOH99-TD-C-111-006.

Disclosures:
No relevant conflicts of interest to declare.