Document text
Principal Investigator: Charlotte M Vines
Organization: UNIVERSITY OF TEXAS EL PASO
Fiscal Year: 2024
Award: $76,750
Funding agency: National Cancer Institute
TITLE: Development of a Mouse model to test targeted therapy to prevent CNS Invasion by Pediatric T-
ALL
Abstract
Leukemia is the most frequent pediatric cancer with acute lymphoblastic leukemia (ALL) being the most common
leukemia type in children. In 15-20% of pediatric T-cell ALL (T-ALL) patients, the cancer invades the Central Nervous
System (CNS), a site which is protected from systemic chemotherapies by the blood brain barrier. The invading leukemic
cells are reservoirs, which can emerge and re-enter the circulation following treatment and cause T-ALL relapse. To
prevent relapse, pediatric patients are treated with cranial irradiation and toxic chemotherapies, which are injected
directly into the CNS. It is not surprising that these treatments can lead to morbid life-long side effects such as reduced
intelligence, stunted growth, and secondary cancers in the CNS. Generally, the T-ALL has entered the CNS prior to
diagnosis, and it is unclear if blocking the entry of T-ALL into the CNS at that point, after they have already entered,
provides any therapeutic benefit. The overarching three goals of this proposal are: 1) to develop a mouse model of T-
ALL that recapitulates human T-ALL, in which we can see the cells in living animals 2) to determine if blocking T-ALL
cells from entering the CNS, prevents further T-ALL CNS invasion and 3) to determine if the T-ALL that has invaded the
CNS will eventually clear the CNS and return to the circulation. Our long-term goal is to reduce or eliminate the need
for damaging intrathecal or cranial treatments in patients with T-ALL. Our studies are based on a human xenograft
mouse model of T-ALL, which revealed that during leukemogenesis, expression of NOTCH1, a transcription factor which
is expressed in more than 80% of pediatric T-ALLs, induces expression of CC chemokine receptor 7 (CCR7). The study
revealed that activation of CCR7 in T-ALL by one of its ligands, CCL19 promotes chemotactic migration of T-ALL into the
CNS. Our proposal is based on a mouse model obtained from Dr. Monica Justice which uses an inducible CCR7(+)ROSA26
floxed-stop-PRDM14 (R26PR) locus. When crossed to an MX1-Cre these R26PR mice develop leukemia in response to
overexpression of NOTCH1, which invades the CNS. Subsequent breeding of these mice with ROSA26 floxed-stop
luciferase mice will result in Cre-recombinase induced expression of bioluminescent luciferase in T-ALL cells. To confirm
a role for CCR7 in the invasion of the CNS, these R26PR mice will be crossed with our own CCR7 conditional knockout
mice (CCR7floxed/floxed (CCR7f/f)) to produce R26PRDM14/CCR7f/f/MX1-CRE mice. Generation of this mouse is aim 1.
Determining which immune cells co-localize with T-ALL cells upon entry into the CNS is aim2 and determining if blocking
CCR7 using the CCL19 antagonist, CCL198-83 prevents or significantly reduces T-ALL CNS invasion, clears the CNS of T-ALL
and increases mouse survival is aim 3. Ultimately, if successful, this mouse model will provide a tool for developing novel
peptide therapies that can block T-ALL CNS invasion, without causing long-term CNS damage in patients and to study
mechanisms of CNS invasion.
Terms: <0-11 years old><Acute Lymphoblastic Leukemia><Acute Lymphocytic Leukemia><Acute Lymphoid Leukemia><Acute T Cell Leukemia><Acute T-Cell Lymphoblastic Leukemia><Acute T-Cell Lymphocytic Leukemia><Acute T-Lymphocytic Leukemia><Animals><Basal Transcription Factor><Basal transcription factor genes><Blood><Blood - brain barrier anatomy><Blood Reticuloendothelial System><Blood-Brain Barrier><Breeding><CC chemokine receptor 7><CC chemokine receptor CCR7><CCL19><CCL19 gene><CCR7 protein><CKb11><CNS Leukemia><CNS Nervous System><CNS lymphatic system><CRE Recombinase><Cancers><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Central Nervous System><Central Nervous System Leukemia><Cephalic><Chemokine Receptor Gene><Child><Child Youth><Childhood ALL><Childhood Acute Lymphoblastic Leukemia><Childhood Acute Lymphocytic Leukemia><Childhood Acute Lymphogenous Leukemia><Childhood Acute Lymphoid Leukemia><Childhood Cancers><Childhood Precursor T Lymphoblastic Leukemia><Children (0-21)><Circulation><Clinical><Complication><Cranial><Cranial Irradiation><Data><Development><Diagnosis><Drosophila Homolog of NOTCH 1><Enterobacteria phage P1 Cre recombinase><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><General Transcription Factor Gene><General Transcription Factors><Generalized Growth><Generations><Goals><Growth><Hemato-Encephalic Barrier><Heterograft><Heterologous Transplantation><Human><IFN><Immune><Immune system><Immunes><Intelligence><Interferons><Intracellular Communication and Signaling><Invaded><Investigators><Justice><KO mice><Knock-out><Knock-out Mice><Knockout><Knockout Mice><L1 Lymphocytic Leukemia><Leukemic Cell><Ligands><LoxP-flanked allele><Luciferase Immunologic><Luciferases><Lymph Node Reticuloendothelial System><Lymph node proper><Lymphatic><Lymphatic nodes><Lymphoblastic Leukemia, Acute, L1><MGC34433><MIP-3b><MIP3B><Macrophage><Malignant Childhood Neoplasm><Malignant Childhood Tumor><Malignant Neoplasms><Malignant Pediatric Neoplasm><Malignant Pediatric Tumor><Malignant Tumor><Malignant childhood cancer><Manuscripts><Mediating><Meninges><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Mouse Strains><Murine><Mus><Mφ><NOTCH1><NOTCH1 gene><Nervous System Injuries><Nervous System Trauma><Nervous System damage><Neuraxis><Neurological Damage><Neurological Injury><Neurological trauma><Null Mouse><Organ><Organism><Outcome><Patients><Pediatric ALL><Pediatric Acute Lymphoblastic Leukemia><Pediatric Acute Lymphocytic Leukemia><Pediatric Acute Lymphogenous Leukemia><Pediatric Acute Lymphoid Leukemia><Peptide Receptor><Peptides><Peripheral><Physicians><Precursor Cell Lymphoblastic Leukemia><Precursor Lymphoblastic Leukemia><Precursor T Lymphoblastic Leukemia><Publishing><Receptor Protein><Regimen><Relapse><Reporting><Research Design><Research Personnel><Researchers><Role><SCYA19><Second Cancer><Second Primary Cancers><Secondary Malignancy><Secondary Malignant Neoplasm><Signal Transduction><Signal Transduction Systems><Signaling><Site><Study Type><T leukemia cell><T-ALL cell><T-Cell Childhood ALL><T-Cell Childhood Acute Lymphoblastic Leukemia><T-Cell Childhood Acute Lymphocytic Leukemia><T-Cell Pediatric ALL><T-Cell Pediatric Acute Lymphoblastic Leukemia><T-Cell Pediatric Acute Lymphocytic Leukemia><T-Cell Type Acute Leukemia><T-Cells><T-Lymphocyte><T-lineage acute lymphoblastic leukemia><TAN1><Testing><Therapeutic><Therapeutic Uses><Tissue Growth><Transcription Factor Proto-Oncogene><Transcription factor genes><Translocation-Associated NOTCH Homolog><Tumor Cell Invasion><Tumor Invasion><Tumor-infiltrating immune cells><Visualization><Xenograft><Xenograft procedure><Xenotransplantation><acute T-cell lymphoblastic leukemia cell><acute T-cell lymphocytic leukemia cell><acute lymphatic leukemia><acute lymphogenous leukemia><acute lymphomatic leukemia><antagonism><antagonist><bacteriophage P1 recombinase Cre><biological signal transduction><bloodbrain barrier><brain irradiation><brain lymph system><brain lymphatic system><brain radiation><cancer in a child><cancer in children><cell type><chemokine receptor><chemokine receptor 7><chemotherapy><child patients><child with cancer><childhood malignancy><conditional knock-out><conditional knockout><cranial radiation><developmental><falls><flow cytophotometry><floxed><floxed allele><glia lymphatic circuit><glia-lymphatic system><glial lymphatic system><glialymphatic circuit><glialymphatic network><glialymphatic pathway><glialymphatic system><glymphatic clearance pathway><glymphatic pathway><glymphatic system><glymphatic-lymphatic system><glymphatics><immune cell infiltration of tumors><immune cells infiltrating the tumor><immune cells that infiltrate the tumor><in vivo><infant ALL><infiltration of tumors by immune cells><intratumoral immune cell><intratumoral immune infiltrate><kids><leukemia><leukemia relapse><leukemogenesis><living system><lymph gland><lymph nodes><lymphnodes><malignancy><meninge><migration><mouse model><murine model><neoplasm/cancer><neurotrauma><novel><ontogeny><overexpress><overexpression><paravascular system><pediatric cancer><pediatric malignancy><pediatric patients><prevent><prevent relapse><preventing><receptor><relapse prevention><response><secondary cancer><side effect><social role><sphingosine 1-phosphate><study design><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><thymus derived lymphocyte><tool><trafficking><transcription factor><tumor immune cell><tumor immune infiltrate><tumor infiltration of immune cells><xeno-transplant><xeno-transplantation><youngster>