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Supplemental Figure 7 from Broad Next-Generation Integrated Sequencing of Myelofibrosis Identifies Disease-Specific and Age-Related Genomic Alterations

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posted on 2024-05-01, 07:21 authored by Malathi Kandarpa, Dan Robinson, Yi-Mi Wu, Tingting Qin, Kristen Pettit, Qing Li, Gary Luker, Maureen Sartor, Arul Chinnaiyan, Moshe Talpaz

Supplemental Figure 7. Differential gene expression in MF with Spleen size >7 cm vs <7 cm. Panel A is a heatmap of the differentially expressed genes, 554 genes upregulated in MF with large spleen and 303 genes downregulated. Panel B is Volcano plot showing log fold change and p value of the genes depicted in A. Panel C shows RNA enrichment analysis shows GO pathways that are down regulated (green) and upregulated (red) in MF with spleen enlargement.

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D. Dan and Betty Kahn Foundation

NIH Division of Cancer Control and Population Sciences

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ARTICLE ABSTRACT

Myeloproliferative neoplasms (MPN) are characterized by the overproduction of differentiated myeloid cells. Mutations in JAK2, CALR, and MPL are considered drivers of Bcr-Abl−ve MPN, including essential thrombocythemia (ET), polycythemia vera (PV), prefibrotic primary myelofibrosis (prePMF), and overt myelofibrosis (MF). However, how these driver mutations lead to phenotypically distinct and/or overlapping diseases is unclear. To compare the genetic landscape of MF to ET/PV/PrePMF, we sequenced 1,711 genes for mutations along with whole transcriptome RNA sequencing of 137 patients with MPN. In addition to driver mutations, 234 and 74 genes were found to be mutated in overt MF (N = 106) and ET/PV/PrePMF (N = 31), respectively. Overt MF had more mutations compared with ET/PV/prePMF (5 vs. 4 per subject, P = 0.006). Genes frequently mutated in MF included high-risk genes (ASXL1, SRSF2, EZH2, IDH1/2, and U2AF1) and Ras pathway genes. Mutations in NRAS, KRAS, SRSF2, EZH2, IDH2, and NF1 were exclusive to MF. Advancing age, higher DIPSS, and poor overall survival (OS) correlated with increased variants in MF. Ras mutations were associated with higher leukocytes and platelets and poor OS. The comparison of gene expression showed upregulation of proliferation and inflammatory pathways in MF. Notably, ADGRL4, DNASE1L3, PLEKHGB4, HSPG2, MAMDC2, and DPYSL3 were differentially expressed in hematopoietic stem and differentiated cells. Our results illustrate that evolution of MF from ET/PV/PrePMF likely advances with age, accumulation of mutations, and activation of proliferative pathways. The genes and pathways identified by integrated genomics approach provide insight into disease transformation and progression and potential targets for therapeutic intervention.

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