MAP2K1(MEK1) is a kinase which is downstream of BRAF and upstream of ERK-1/-2 in the MAPK pathway. MAP2K1 missense mutations and small in frame deletions have been reported in approximately 50% of hairy cell leukemia-variant (HCL-variant) cases, regardless of IGHV4-34–status, and greater than 50% of cases of IGHV4-34–positive classic hairy cell leukemia (classic HCL). These mutations are predicted to increase the basal enzymatic activity. MAP2K1 mutations appear to be mutually exclusive of the BRAF p.Val600Glu mutation, which appears to be largely specific to IGHV4-34–negative, classic HCL. Nevertheless, MAP2K1 mutations have been described as a mechanism of resistance to targetted therapy with BRAF inhibitors. The MAPK pathway alterations are potentially targetable.

MAP2K1 mutations result in constitutive ERK phosphorylation and may be associated with higher resistance to MEK inhibitors. However these inhibitors are currently undergoing clinical trials and their efficacy and/or lack of toxicity has not yet been demonstrated.

The p.C121S mutation has been associated with resistance to mutant BRAF inhibitors.

This gene is a known cancer gene.

This gene is a known cancer gene.