Thus, downregulation of p27 activity, through genetic disruption19 and/or reduction of protein expression52 potentially induced by BRAF-MEK-ERK signaling itself,57 may facilitate HCL clonal expansion driven by mutant BRAF. It is worth noting that CDKN1A/p21, another cyclin-dependent kinase inhibitor promoting senescence,58 can be a direct target of the KLF2 transcription factor,59,60 which is also mutated (and perhaps functionally impaired) in some patients with HCL. This evidence concerns the gene BRAF and hairy cell leukemia.