Theoretical model of chronic myeloid leukemia. BCR-ABL1 fails to transform cells lacking inherent self-renewal potential, thus supporting the notion of CP CML as an HSC disorder. HSCs, through successive accumulation of preleukemic genetic abnormalities (eg, BCR-ABL1 expression, BCL-2 overexpression, or loss of JUNB or ICSBP expression), acquire a proliferative and survival advantage and lose the ability to undergo apoptosis. Further genetic and/or epigenetic events in BCR-ABL1–positive committed myeloid cells (eg, common myeloid progenitors [CMP] and granulocyte-monocyte progenitors [GMP]) endow the latter with self-renewal potential (eg, aberrant β-catenin activation) and arrest myeloid differentiation (eg, loss of CEBPα or IKZF1 expression), thus facilitating the emergence of a leukemic stem cell (LSC) clone driving the transition to blast-phase CML (partially adapted from Weissman⁹⁴ ).