Cell State Transitions Drive the Evolution of Disease Progression in B-Lymphoblastic Leukemia

Cancer stem cells (CSC) are hypothesized to promote tumor progression through innate chemoresistance and self-renewal. CSCs reside in the CD34+/CD38- immunophenotypic subpopulation of acute myeloid leukemia (AML). Isolation of CSCs from B-lymphoblastic leukemia (B-ALL) has proven difficult, and the cells of interest apparently are not isolated to the CD34+/CD38- compartment. This may be explained, in part, by temporal variations of CD34 and CD38 expression which result in stochastic cell state transitions (e.g., from CD34+/CD38+ to CD34+/CD38-). We present a mathematical model of these transitions and correlate salient findings with BCR::ABL1 status, minimal residual disease (MRD), and relapse in adult B-ALL. As the CSC hypothesis is well supported in AML, we focus on transitions to and from the hematopoietic stem cell compartment (CD34+/CD38-). Our analysis suggests the presence of dedifferentiating transitions to a CD34+/CD38- stem cell-like immunophenotype, especially in B-ALL with BCR::ABL1. In contrast, BCR::ABL1-negative patient samples have low CD34+/CD38- self-renewal rates and either high CD34+/CD38+ or CD34-/CD38+ incoming rates. High CD34+/CD38- self-renewal is also associated with positive MRD following induction chemotherapy. We find a lack of observable changes in cell state transitions between diagnosis and relapse specimens. Furthermore, simulated therapies targeting the stem cell-like compartment indicate that blocking transitions to the CD34+/CD38- state (i.e., blocking dedifferentiation) is more effective than promoting transitions from the CD34+/CD38- state toward other states (i.e., promoting differentiation) to reduce the proportion of CD34+/CD38- cells. The modeling framework used here is a novel, useful tool to infer prognosis and genotype from routine flow cytometry.

Flow cytometry characterization of B-ALL samples (diagnosis, remission, and relapse) is used to parameterize a mathematical model of cell state transition rates and stratify patients for post-induction chemotherapy MRD.