Abstract
Current monitoring of acute lymphoblastic leukemia (ALL) in living mice is based on FACS analysis of blood hCD45+ cells. In this work, we evaluated the use of human IGFBP2, B2M or Hsp90 as soluble markers of leukemia. ELISA for B2M and IGFBP2 resulted in high background levels in healthy animals, precluding its use. Conversely, plasma levels of Hsp90 showed low background and linear correlation to FACS results. In another experiment, we compared Hsp90 levels with percentage of hCD45+ cells in blood, bone marrow, liver and spleen of animals weekly sacrificed. Hsp90 levels proved to be a superior method for the earlier detection of ALL engraftment and correlated linearly to ALL burden and progression in all compartments, even at minimal residual disease levels. Importantly, the Hsp90/hCD45+ ratio was not altered when animals were treated with dexamethasone or a PI3K inhibitor, indicating that chemotherapy does not directly interfere with leukemia production of Hsp90. In conclusion, plasma Hsp90 was validated as a soluble biomarker of ALL, useful for earlier detection of leukemia engraftment, monitoring leukemia kinetics at residual disease levels, and pre-clinical or mouse avatar evaluations of anti-leukemic drugs.
Highlights
Patient-derived tumor xenografts mouse models has been largely used for the study of cancer biology, pre-clinical test of new drugs or new drug combinations, and more recently as avatars to pursue personalized therapeutic regimens [1]
Beta-2-microglobulin (B2M), insulin-like growth factor binding protein 2 (IGFBP2) and heat shock protein 90 (Hsp90) were selected as candidate soluble biomarkers of acute lymphoblastic leukemia (ALL) based on their very high level of expression and extracellular secretion or release by leukemia cells [16,17,18,19,20,21,22,23] and for the availability of commercial Enzyme-linked immunosorbent assay (ELISA) kits. Analysis of these biomarkers levels quantified by ELISA, in plasma of healthy nonobese diabetic (NOD)/SCID mice versus mice transplanted with primary T-cell ALL (T-ALL), showed unacceptably high levels of B2M and IGFBP2 in healthy animals, suggesting antibodies cross-reactivity with the human and mouse biomarker
Human Hsp90 levels were clearly higher in animals injected with ALL in comparison to healthy controls, even at the lowest percentage of human leukemia cells in the mice peripheral blood, which in this experiment was 0.5% (Fig 1A)
Summary
Patient-derived tumor xenografts mouse models has been largely used for the study of cancer biology, pre-clinical test of new drugs or new drug combinations, and more recently as avatars to pursue personalized therapeutic regimens [1]. Mice were transplanted with a primary ALL cells and weekly monitored for ALL by flow cytometry and or ELISA Hsp90. The number of human CD45+ cells in peripheral blood mononuclear cells and plasma levels of the ELISA biomarker (B2M, Hsp90 or IGFBP2) was measured at different time points, before and/or during treatment.
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