Here, we developed genetically engineered mouse models (GEMMs) of CRLF2/JAK2 mutant B-ALLs and used a pharmacogenomics approach to delineate the functional role of JAK2 in these leukemias and human CRLF2-rearranged/JAK2I682F-expressing MHH-CALL4 B-ALLs. Here, CRLF2 is linked to leukemia.