Whole-exome sequencing detected clonal selection and outgrowth of the acquired resistant tumors and, in two of the four patients, revealed resistance-associated loss-of-function mutations in the genes encoding interferon-receptor-associated Janus kinase 1 (JAK1) or Janus kinase 2 (JAK2), concurrent with deletion of the wild-type allele. A truncating mutation in the gene encoding the antigen-presenting protein beta-2-microglobulin (B2M) was identified in a third patient...In Patient 3, whole-exome sequencing of the baseline and progressive lesions showed a 4-bp S14 frame-shift deletion in exon 1 of the beta-2-microglobulin component of MHC class I as 1 of only 24 new relapse-specific mutations and the only such mutation that was homozygous.