Joe Wiemels UCSF California Childhood Leukemia Study New research using archived DBS

 These data were presented (in draft form ) at the Brocher Symposium in March  If validated,  they provide the first quantitative glimpse of what may be one of the antecedents of childhood leukemia.  modifiers of conversion to leukemia may be more rapidly identified; and  surveillance and ultimately intervention to prevent ALL may be possible.

DBS are a unique ‘common data element’ collected  at the same time (1-3 days post delivery)  in the same way (heel stick)  using the same instrument (filter paper)  only storage conditions differ They also contain  child’s blood only  multiple other analytes which reflect pre-natal conditions  DNA, hemoglobin, albumin, cytokines, nutritional status

Combined OR = % CI = Urayama et al., 2010

6 “Physician diagnosed” infection is a RISK factor, NOT protective factor

Children with leukemia have lower prior exposure to infection. When they contract infection, children who get leukemia respond more strongly to the infection and go to the doctor more often. Are children who get leukemia born with differently-tuned immune systems?

CEBP 20(8);1-5.E2011

Hypothesis: children who grow up to get leukemia have a detectably different immune cytokine profile at birth. 116 leukemia (ALL) case Guthrie cards, 116 birthdate, gender, and ethnicity-matched controls Protein extracts from cards, analyzed by Luminex Th1: IL2, IL12(p70), IFN-γ, TNF-α Th2: IL4, IL5, IL10, IL13 Th17: IL17, IL6 Other: GM-CSF Only 5 were detectable: IL4, IL6, IL10, IL12, IL13

 Cases and controls were identical in the distributions of sex (61% male) and race/ethnicity (48% Hispanics, 33% non-Hispanic whites, and 19% others).  Cases and controls were similar in age (mean age in years: 3.8 for cases and 3.9 for controls, P=0.8), but controls had a higher proportion of subjects who had an annual household income greater than $75,000 compared with cases (50% vs. 38%, P=0.11).  Eleven 11 cytokines measured  5 (IL4, IL6, IL10, IL12, & IL13) were detectable.

 IL4, IL6, IL10, and IL13 were significantly lower among childhood ALL cases than controls  Adjusting for the potential confounders  Increasing levels of IL4, IL6, IL10, and IL13 were all associated with a significantly decreased risk of childhood ALL.

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 All 5 cytokines  Same statistical model  Only IL10 remained statistically significant.

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 Use the lowest tertile of IL10 level as referent group  Second tertile had an OR of 0.16 (95% CI: 0.07 – 0.39)  Third (highest) tertile had an OR of 0.04 (95% CI: )  This represents a 25-fold difference

16 Produced by Monocytes, Regulatory T-cells, and B-1 cells Suppresses inflammatory Th1-type responses and enhances B-cell development and function Critical role in pregnancy – suppression of the immune rejection of the fetus

17 Children who get ALL are profoundly deficient in IL10 at birth This congenital defect may make them more susceptible to strong reaction from infections, and increased risk of leukemia.

“In summary, our data suggest that children who develop leukemia may already have dysregulated immune function at birth. Future studies need to confirm this association and consider maternal and genetic factors in the development of childhood leukemia through their influence on the child’s immune development.”