JAK2

Overview

First described 1997. Earliest sequence paper UniProt cites for the protein: Peeters et al, Blood, 1997, "Fusion of TEL, the ETS-variant gene 6 (ETV6), to the receptor-associated kinase JAK2 as a result of t(9;12) in a lymphoid and t(9;15;12) in a myeloid leukemia". Source.

• Lymphoma, JAK-STAT, in NK/T-cell lymphoma and in Hodgkin lymphoma: STAT3 and STAT5B mutations lock the transcription factor in its phosphorylated form. The STAT5B N642H substitution increases the binding affinity of the phosphotyrosine for the mutant histidine, so the phosphorylated protein persists and binds its target sites far more, and the growth advantage it gives can be partly reversed by a JAK1/2 inhibitor in the laboratory (Kucuk 2015). In Hodgkin lymphoma and primary mediastinal B-cell lymphoma the pathway is switched on from the other end, by amplification of JAK2 inside the 9p24.1 amplicon and by loss of the brakes SOCS1 and PTPN1. Frequency: Activating STAT3 and STAT5B mutations across 51 NK/T-cell lymphomas and 43 gamma-delta T-cell lymphomas, with STAT5B N642H particularly frequent in the gamma-delta group (Kucuk 2015). JAK2 sits in the 9p24.1 amplicon in Hodgkin lymphoma and mediastinal large B-cell lymphoma, and its amplification raises both protein and activity and specifically induces PD-1 ligand transcription (Green 2010). What it changes about treatment: Not through an approved drug. JAK inhibitors have been tested in both settings without becoming standard; the practical consequence of the Hodgkin and mediastinal finding is that it explains why checkpoint blockade works there.
• Lymphoma, 9p24.1 amplification of CD274, PDCD1LG2 and JAK2: The amplicon contains the genes for both PD-1 ligands and the kinase that induces them, so a single copy-number event raises the ligands twice over, by gene dose and by JAK2-driven transcription (Green 2010). It is the clearest example in oncology of a tumour genetically buying its way out of T-cell attack. Alongside it, CIITA, the master transactivator of MHC class II, is broken by recurrent fusions, which lowers class II on the tumour cell and, in the same rearrangements, places PD-L1 and PD-L2 under new promoters. Frequency: In 108 newly diagnosed classical Hodgkin lymphomas evaluated by fluorescence in situ hybridisation, 97% had concordant alterations of both loci: polysomy in 5% (5 of 108), copy gain in 56% (61 of 108) and amplification in 36% (39 of 108), and higher-level gain predicted shorter progression-free survival (Roemer 2016). Genomic CIITA breaks in 38% of primary mediastinal B-cell lymphomas and 15% of classical Hodgkin lymphomas across 263 B-cell lymphomas (Steidl 2011). What it changes about treatment: Yes, and it is the reason for the sharpest contrast in lymphoma immunotherapy. PD-1 blockade produced an objective response in 20 of 23 heavily pre-treated Hodgkin patients, 87%, in the first study, in a disease where most had already failed both transplant and brentuximab vedotin (Ansell 2015); in B-cell non-Hodgkin lymphoma outside the mediastinal group, single-agent checkpoint blockade does very little. Nothing is tested before a Hodgkin patient is given a checkpoint inhibitor, because the alteration is nearly universal.