Emerging evidence implicates infectious exposure in the pathophysiology of B-cell acute lymphoblastic leukemia (B-ALL) in individuals with heterozygous germline mutations in the PAX5 gene. Among the ongoing research exploring associated mechanisms to inform the development of preventive therapies for this patient population, results of a preclinical study published in March 2022 in Cancer Research point to inhibition of the JAK-STAT pathway as a promising strategy.1
In otherwise healthy Pax5+/- mice, the transformation from the latent preleukemic phase to overt B-ALL is “mediated by the appearance… of an aberrant IL7- sensitive progenitor compartment that is susceptible to malignant transformation through accumulation of secondary mutations in the JAK/STAT pathway” upon exposure to infectious pathogens, the researchers wrote in their report.1
In previous rodent models, the authors found that in vitro administration of the JAK1/2 inhibitor ruxolitinib increased cell death of IL7-dependent pro-B cells, especially in cells from Pax5+/- mice vs wild-type mice.2 In the present study, they investigated whether in vivo ruxolitinib treatment could prevent the development of infection-driven B-ALL in Pax5+/- mice upon exposure to a natural infectious environment.1
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Pax5+/- mice and wild-type control mice received food pellets with or without ruxolitinib for 14 or 28 days. For the pellets containing ruxolitinib, the optimal formulation contained 0.75 grams per kilogram of food, corresponding to a dose of approximately 120 mg/kg/day.1
Compared to untreated age-matched Pax5+/- littermates, the Pax5+/- mice treated with ruxolitinib showed significant reductions in pro-B and pre-B cells in the bone marrow on day 14 of treatment (P =.0003), with more pronounced changes noted on day 28 (P <.0001). Reductions in pro-B and pre-B cells were also observed in ruxolitinib-treated wild-type mice on day 28 (P =.0018).1
In treated 1-year-old Pax5+/- mice that did not develop B-ALL, the precursor B-cell population was similar to that of treated 1-year-old wild-type mice after 28 days, consistent with the authors’ previous findings.1,2 The current results further suggest that the reduction in preleukemic B cells was driven by a cell autonomous mechanism rather than changes in serum cytokine concentrations.
Only 1 of the 29 (3.44%) Pax5+/- mice receiving ruxolitinib for 28 days developed and died from B-ALL after exposure to an infectious environment, compared to 8 of 24 (23.52%) untreated Pax5+/- mice (P .0332). Notably, the incidence of B-ALL in Pax5+/- mice treated for 14 days (2/8, 25%) was similar to that of untreated Pax5+/- mice.1
“Thus, ruxolitinib treatment reduces B-ALL risk, with leukemia prevention occurring in a time-dependent manner, presumably to ensure eradication of maximal numbers of susceptible immature B cells,” the authors concluded. “These findings support the hypothesis that children who are genetically predisposed to B-ALL might similarly benefit from early transient JAK/STAT pathway inhibition as a preventive strategy.” In addition, this treatment approach may hold value in the prevention of other forms of ALL.1
To glean perspectives from physician-scientists on the topic, Hematology Advisor interviewed Sarah K. Tasian, MD, chief of the Hematologic Malignancies Program in the division of oncology at Children’s Hospital of Philadelphia and associate professor of pediatrics at the Perelman School of Medicine at the University of Pennsylvania; and Kelly Maloney, MD, a pediatric hematologist and oncologist at Children’s Hospital Colorado and associate professor of pediatrics in the section of hematology, oncology, and bone marrow transplantation at the University of Colorado Denver, Anschutz Medical Campus in Aurora.
