A transient dephosphorylation of JAK1 and JAK2 characterises the early-phase response of murine erythroleukemia cells to the differentiation inducer hexamethylenebisacetamide

Although dephosphorylation of tyrosine containing proteins is considered a necessary step in the induction of leukemia cell differentiation by hybrid polar compounds (HPC), the crucial actors in this step remain unknown. We p resent evidence that tyrosine phosphorylation of JAK1 and JAK2 is down-regu lated in murine erythroleukemia cells (MELC) within the first 6 h of their exposure to the prototype of the HPC family, hexamethy-lenebisacetamide (HM BA), with full recovery at 14 h. Further evidence that the JAKs-centered si gnalling pathway is switched off early by HMBA was provided by the demonstr ation that STAT5, a downstream member of this pathway, turned out to be com pletely dephosphorylated at 6 h in HMBA-treated cells. This JAKs dephosphor ylation did not occur in HMBA-resistant clones, suggesting that JAKs are po ssible targets of the dephosphorylative process required for leukemia cell commitment to differentiation. These results may have impact on leukemia th erapy based on JAKs inhibitors.