The promise of Janus kinase inhibitors in the treatment of hematological malignancies

Abstract

The Janus kinases (JAK) are a family of kinases that play an essential role in cytokine signaling and are implicated in the pathogenesis of autoimmune diseases and hematological malignancies. As a result, the JAKs have become attractive therapeutic targets. The discovery of a JAK2 point mutation (JAK2 V617F) as the main cause of polycythemia vera lead to the development and FDA approval of a JAK1/2 inhibitor, ruxolitinib, in 2011. This review focuses on the various JAK and associated components aberrations implicated in myeloproliferative neoplasms, leukemias, and lymphomas. In addition to ruxolitinib, other JAK inhibitors are currently being evaluated in clinical trials for treating hematological malignancies. The use of JAK inhibitors alone or in combination therapy should be considered as a way to deliver targeted therapy to patients.

Mutant JAK3 phosphoproteomic profiling predicts synergism between JAK3 inhibitors and MEK/BCL2 inhibitors for the treatment of T-cell acute lymphoblastic leukemia

“…To this end, an in vivo patient-derived xenograft model was established with T-ALL sample 389E that carries a JAK3 (M511I) mutation. For these studies, the JAK1-selective inhibitor ruxolitinib was used due to its known side effect profile and known efficacy in other hematological disorders 27 in combination with ABT-199. To accurately detect synergism, suboptimal concentrations were used for ABT-199 (20 mg/kg/day/PO) and ruxolitinib (40 mg/kg/day/PO), which were 70–80% reduced compared with previously published studies when used as a single agent.…”

Inhibiting Janus Kinase 1 and BCL-2 to treat T cell acute lymphoblastic leukemia with IL7-Rα mutations

“…The treatment and cure rates of childhood ALL is considered a major medical success of the 20th century; current treatment protocols result in a five-year overall survival rate of up to 90% in pediatric patients. Despite this progress, there is a great need for a more targeted and less toxic approach to treating hematological malignancies in growing children [ 40 ]. With an enhanced understanding of the molecular signatures of these cancers, the current challenge for clinicians will be deciding when it is appropriate to supplement the chemotherapy regimen with targeted drugs, or replace conventional therapeutics all together.…”

Fusion of the genes ataxin 2 like,ATXN2L, and Janus kinase 2,JAK2, in cutaneous CD4 positive T-cell lymphoma

“…However, the PCM1-JAK2 fusion which was reported in a patient with peripheral T-cell lymphoma [ 15 ], the amplification of JAK2 which was found in 12.5% of cutaneous T-cell lymphomas [ 23 ], and the present ATXN2L-JAK2 fusion gene indicate that JAK2 is recurrently involved in T-cell lymphomagenesis albeit at as yet unknown frequency. The clinical importance of detecting JAK2 -fusion genes and proteins is connected with the detection of new targeted molecular therapies that may be effective in such patients [ 20 ]. Van Roosbroeck [ 16 ] found a SEC31A-JAK2 fusion in classical Hodgkin lymphoma and showed that SEC31A-JAK2 Ba/F3 transformed cells were sensitive to treatment with JAK2 inhibitors.…”

“…Both PCM1-JAK2 and SEC31A-JAK2 encode constitutively activated tyrosine kinases [ 15 , 16 ]. It is important to detect and report JAK2 fusions, regardless of the diagnosis, because such cases could be responsive to treatment with JAK2 inhibitors [ 17 – 20 ].…”