Studies of monozygotic twins with concordant leukemia and scrutiny of archived neonatal blood by polymerase chain reaction (PCR) indicated that many pediatric leukemias are initiated prenatally by chromosomal translocation followed by a variable postnatal period before diagnosis of disease. The latter is thought to reflect a persistent preleukemic stage and a requirement for secondary genetic events. We sought to examine this further by examination of blood spots in rare cases of MLL fusion-positive or ETV6/RUNX1 (TEL-AML1) fusion gene-positive acute leukemia that were diagnosed at ages beyond the normal age range. We present evidence that the duration of the postnatal preleukemic state can occasionally be very protracted in these biological subtypes of pediatric leukemia, and we discuss its biological significance.
In contrast to gene therapy of solid tumors, only a few preclinical studies exist about gene therapy of acute lymphoblastic leukemia. Previously, we showed that vaccination of mice with syngeneic BCR-ABLp185 expressing leukemia cell lines modified to express costimulatory molecules and cytokines induce a systemic immunity against wild type leukemia. However, the difficulties to culture and transfect human leukemia cells limit the clinical application of leukemia cell based vaccines. Thus, we evaluated the pre-immunization of mice with DNA based vaccines subsequently challenged by the cell line BM185. In order to avoid the limitations and serious side effects associated with viral vectors we used nonviral gene delivery methods. Minimalistic immunogenically defined gene expression (MIDGE) vectors encoding a BCR-ABLp185 fusion specific peptide or GM-CSF were used as DNA vaccine and double stem-loop immunomodulators (dSLIM), containing three CpG-motifs were used as immune adjuvant. We provide biometrical and CTL data that shows specific immunization and protection of mice which received the complete vaccine BCR-ABL/GM-CSF/dSLIM by GeneGun delivery of naked DNA. Mean tumor-free survival (p=0.019) and overall survival (p=0.008) were significantly longer compared to non-vaccinated mice. Furthermore we show that BCR-ABL specific sequences are required to prevent Ph+ acute lymphoblastic leukemia by DNA vaccination. However, survival rate was moderate and only 26.7% of vaccinated mice survived and remained tumor-free. While current nonviral genetic tumor vaccine systems are less effective than viral vaccines, in particular when tumor associated antigens are weakly immunogenic, microencapsulation of tumor-specific DNA with poly (β-amino esters) might be a promising, safe and efficient nonviral delivery method for genetic vaccines. These biodegradable cationic polymers can bind and condense DNA into nanoparticles, deliver large DNA payloads and show low toxicity. Therefore, we prepared DNA-polymer complexes of MIDGE-vectors and end-modified poly (butane diol diacrylate co amino pentanol) C32-117 or C32-118 which self-assemble into particles with effective diameters of 200 nm and zeta potentials of 9.8 mV in PBS. We compared the immunization of mice receiving the vaccine BCR-ABL/GM-CSF/dSLIM by intradermal injection as naked DNA or alternatively, complexed with C32-117 or C32-118. We present data about tumor growth, survival rate, tumor free and overall survival of vaccinated and control mice.
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