(A) In B cell malignancies, treatment resistance occurs via two evolutionary models: A Darwinian model for treatment resistance occurs when a preexisting mutation confers resistance and is selected for during treatment, e.g., selection by chemotherapy for TP53 mutations and/or deletions. Alternatively, a Lamarckian model predicts that an oncotherapeutic can directly trigger adaptive responses in malignant cells. The baseline MTF configuration of the cells constrains the range of adaptive shifts, which are propagated to daughter cells via epigenetic mechanisms. Notably, both models can act concurrently. (B) Coordinated shifts in the expression of lineage MTFs and surface receptors occur during normal B cell lineage differentiation. Treatments that target CD19 or BTK affect inputs into the lineage MTF circuit and may alter malignant phenotypes in a pattern dictated by the baseline MTF configuration and B cell lineage differentiation. (C) CD10 and CD19 are expressed at different stages in B cell lineage differentiation and present targeting opportunities. B cells undergoing differentiation that have been targeted by CD19 treatments may shift phenotypes to confer resistance but remain susceptible to alternative targeted therapies such as anti-CD10.