Session: 634. Myeloproliferative Syndromes: Clinical and Epidemiological: Poster I
Hematology Disease Topics & Pathways:
Research, Clinical Research, Diseases, Myeloid Malignancies
Among 234 pre-PMF patients, 135 (57.7%) harbored JAK2V617F, 36 (15.4%) CALR and 3 (1.3%) MPL mutations; 60 (25.6%) patients were negative for all three mutations. JAK2V617F-mutated patients were older (P=0.036), had more constitutional symptoms (P=0.027) and cardiovascular risk factors (P=0.045), higher white blood cell count (WBC) (P<0.001), hemoglobin level (HB) (P<0.001), neutrophile granulocyte (NEU) (P<0.001), eosinophilic granulocyte (EOS) (P<0.001), basophilic granulocyte (BAS) (P<0.001), hematocrit (HCT) (P=0.002) and red blood cell distribution width (RDW) (P<0.001) (Figure A). CALR-mutated cases had higher platelet hematocrit (PCT) (P=0.043) and lactic dehydrogenase (LDH) (P=0.008). Besides, CALR group had a higher proportion of 25.0% to progress to overt-PMF than JAK2V617F group (9.6%) and TN group (6.7%) (P=0.025) (Figure A).
As for risk factors of progression to overt-PMF, univariable analysis found it was associated with mean platelet volume (MPV) (P=0.019), HB (P=0.027), WBC (P=0.008), LDH (P=0.004) and CALR mutations (P=0.007). Multivariable analysis revealed that lower HB value (P=0.041; HR 0.981, 95% CI 0.962-0.999) and CALR mutation (P=0.001; HR 3.716, 95% CI 1.331-10.069) had negative impact on the progression to overt-PMF (Figure B). When divided by HB with cut-off point of 128 g/L, patients with HB value ≤128 g/L were more likely to progress to overt-PMF compared to >128 g/L groups (P=0.007) (Figure C). And patients carried CALR mutation were also more likely to progress to overt-PMF (P<0.001) (Figure D).
We performed next-generation sequencing (NGS) in 18 pre-PMF patients, including 9 JAK2V617F, 3CALR and 6 TN, 3 of which progressed to overt-PMF and 15 stayed in pre-PMF until the end of the follow-up. JAK2V617F was the most frequently mutated gene (9/38, 23.7%), followed by TET2 (7/38, 18.4%), RELN (4/38, 10.5%) and ASXL1 (3/38, 7.9%). JAK2V617F-mutated patients possessed more mutations related to activation signaling pathway (P=0.025) and DNA methylation (P=0.033) (Figure F). TN patients possessed more mutations related to transcription factor (P=0.048) (Figure F). Patients who progressed to overt-PMF possessed more mutations associated with myeloid related transcription factor (P=0.025) (Figure H). We further performed RNA-Seq analysis in 6 pre-PMF samples and 14 overt-PMF samples. Compared to pre-PMF, overt-PMF showed 49 up-regulated and 13 down-regulated differentially expressed genes (DEGs), of which CSCF3 and CXCL13 were significantly up-regulated (Figure I,J). Gene ontology (GO) functional enrichment analysis showed that DEGs were enriched in cell-cell signaling, cytokine activity, monocyte chemotaxis and chemokine activity (Figure K). KEGG biofunctional analysis showed that DEGs were significantly enriched in cytokine-cytokine receptor interaction, chemokine signaling pathway, IL-17 signaling pathway and NF-kappa B signaling pathway (Figure L).
In conclusion, CALR-mutated pre-PMF patients with HB value ≤128 g/L were more likely to progress to overt-PMF. Genetic analysis found patients with high proportion of progress to overt-PMF tended to possess mutations associated with myeloid related transcription factor. And the upregulation of CSCF3 and CXCL13 may potentially drive the progression of overt-PMF in pre-PMF patients through inflammatory and cytokine related pathways.
Acknowledgement: This research was funded by the Key R&D Program of Zhejiang, No. 2022C03137; Public Technology Application Research Program of Zhejiang, China, No. LGF21H080003; Zhejiang Medical Association Clinical Medical Research special fund project, No. 2022ZYC-D09.
*Correspondence to: Jian Huang, M.D., Ph.D., Department of Hematology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang, China. E-mail: househuang@zju.edu.cn
Disclosures: No relevant conflicts of interest to declare.
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