ADIPOSE TISSUE IMPAIRS THE TREATMENT OF LEUKEMIA
S D Mittelman, J W Behan, J P Yun, A M Butturini, S G Louie, N Heisterkamp, Childrens Hospital Los
Angeles, Los Angeles, CA
Background. Obesity increases the risk and mortality of several types of cancer. We have reported that
obese children with high-risk acute lymphoblastic leukemia (ALL) had a 50% higher relapse rate than lean
children. We recently found that leukemia in obese mice is more resistant to chemotherapy than that in
nonobese mice. Hypothesis. We hypothesize that adipocytes directly impair chemotherapy.
Design/Methods. We developed a novel co-culture system in which murine leukemia cells (8093s) are
grown separated by a porous membrane from adipocytes (differentiated 3T3-L1 cells) or fibroblasts
(undifferentiated 3T3-L1s). We also cultured 8093s in adipocyte-conditioned media (ACM) or fibroblastconditioned media (FCM). Results. Adipocytes decreased the cytotoxicity of all chemotherapies tested (see
table). The presence of ACM protected 8093s from 72 hours of 25 nM dexamethasone: in ACM, there were
10924% of the original cell number remaining, compared to regular media (4012%) or FCM (6617%,
p<0.05). ACM did not impair vincristine, AMN107, or daunorubicin (not shown). Media conditioned by
both adipocytes and 8093s together did protect 8093s from 72 hours of 35 nM daunorubicin; there were
>10 times as many viable 8093s in this media (1.3  0.3 x 106) as the other media types (all <13,000, n=3,
p<0.05 for all comparisons). Conclusions. Our data demonstrate that adipocytes engender ALL protection
from chemotherapy in vitro. Adipocytes likely secrete at least 2 factors that increase ALL resistance. We
also find evidence of a two-way communication between leukemia cells and adipocytes that promotes
leukemia survival. These results may partly explain the higher relapse rate of ALL in obese children.
Table: Viable cellsSEM (x1000) after 3-day exposure to chemotherapy in transwells
No Feeder
Fibroblasts
Adipocytes
Vincristine (5 nM, n=5)
19.22.8
64.413.2
106.415.9
Dexamethasone (25 nM, n=5)
21.713.6
28.76.6
65.016.1
AMN107 (20 nM, n=5)
112.838.9
96.539.2
182.857.9
Daunorubicin (35 nM, n=3)
1.90.1
38.09.5
322.230.8
L-Asparaginase (0.6 IU/mL, n=2)
169.00.7
173.59.9
317.824.4
p value (A vs. F)
<0.01
<0.01
<0.01
<0.01
n/a