Figure 1.

(a) Somatic mutations of the autophagy network in patients with myeloid neoplasms. Whole exome and targeted sequencing identified 55 somatic mutations in autophagy-related genes (a complete list of mutations is presented in Table 1). A schematic diagram illustrates mutations per patients (N=40; pts #1-31; our cohort; pts #32-40, TCGA cohort). For pt #1, exome sequencing was performed at the stage of MDS and AML. Different colors represent the specific pathways where genes were clustered based on their function in the autophagy pathway (yellow: early stage autophagy; gray: vesicles-mediated transport; light blue: lysosomal enzymes: red: protein kinases and dependent kinases family; purple: protein tyrosine phosphatase family; black: phosphatidylinositol-3 phosphatases; green: apoptotic inducers/inhibitors; dark green: insulin receptor/mTOR associated signaling. Clustering was conducted by reviewing previous published reports and by using the reactome pathway database (http://www.reactome.org/). Pink half square triangles represent patients who were hemizygous for specific mutations. Stars indicate genes for which germline variants were also detected. The total number of mutations per pathway is indicated in the right column. (b) Schematic diagrams of two mutated autophagy-related genes. Protein kinase cAMP-activated catalytic subunit beta (PRKACB) is a serine/threonine protein kinase composed by 351 amino acids which mediates signaling through cyclic AMP and it is involved in the induction of autophagy. The protein kinase (PK) domain spans amino-acid 44-244. Three patients in our cohort carried PRKACB mutations [p.W184C, p.W244R, Splice site_303 (exon 9-1)]. Unc-51 like kinase 4 (ULK4) is a serine/threonine protein kinase involved in autophagy. The protein is composed by 1275 amino acids with a kinase domain spanning amino acids 4-280. Two patients carried ULK4 mutations (p.L1220X, p.P1003L).

(c) Mutational spectrum of patients with myeloid neoplasms harboring mutations in the autophagy network. A schematic diagram illustrates the complete molecular profile of patients with myeloid malignancies (N=40; pts #1-31; our cohort; pts #32-40, TCGA cohort). For pt #1, exome sequencing was performed at the stage of MDS and AML. Data are a collection of exome sequencing, TruSeq analysis, and Sanger sequencing. Genes were clustered in pathway based on their function according to the literature (blue: DNA-methylation; light green: Chromatin modification; dark green: transcriptional factors/repressors/regulation; purple: RNA-helicases; light orange: signal transduction/receptors; yellow: cohesin complex; dark orange: RNA-splicing). Pink half square triangle represents patients who are hemizygous for specific mutations.