This patient is most likely to have a BCR-ABL genetic mutation predisposing him to chronic myeloid leukemia (CML). He has the classic presentation for CML with the insidious onset of fatigue; early satiety and progressive weight loss associated with splenomegaly; and a peripheral blood smear demonstrating myelocytes, metamyelocytes, and basophils. The peripheral blood smear of CML is commonly described as mimicking a bone marrow aspirate. Basophilia is a general clue to the presence of a myeloproliferative neoplasm (MPN).

IGH/CD1 is the mutation associated with mantle cell lymphoma (MCL). MCL can present with hyperleukocytosis and massive splenomegaly, but myeloid precursors and basophilia would not be seen on peripheral blood smear.

The JAK2 gene mutation is associated with polycythemia vera, essential thrombocytosis (ET), and primary myelofibrosis but not CML. Because CML is a more likely diagnosis, especially because of the prominence and degree of leukocytosis, BCR-ABL mutation should be excluded first in this patient.

PML-RAR protein mutation is associated with acute promyelocytic leukemia (APL). APL does not demonstrate basophilia or transitional myeloid precursors on the peripheral blood smear. Additionally, it is clinically associated with disseminated intravascular coagulation and thrombocytopenia rather than thrombocytosis, and splenomegaly is uncommon in APL.