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Principal Investigator: Lynn Hua Lee
Organization: CINCINNATI CHILDRENS HOSP MED CTR
Fiscal Year: 2024
Award: $196,112
Funding agency: National Cancer Institute
Proposal Summary/Abstract:
Though outcomes for pediatric acute leukemia have improved dramatically over the last few decades, infant
leukemia is a particularly aggressive disease which remains difficult to cure even with chemotherapy
intensification and bone marrow transplant. Most of these leukemias carry a rearrangement of the MLL gene,
a phenomenon also seen in some de novo acute myeloid leukemias (AML) as well as therapy-related AML,
and studies have demonstrated that a common gene expression program underlies these leukemias
regardless of lineage. Through preliminary studies, we have found that MLL-fusion leukemias express high
levels of MBNL1, an RNA binding protein that regulates alternative RNA splicing. We have also identified an
alternative splicing (AS) signature unique to MLL-fusion leukemia, and show that MBNL1 loss causes reversion
of this signature and impairs MLL-fusion leukemia cell growth. We thus hypothesize that MBNL1 is a critical
regulator of an MLL-fusion specific AS program, and that disruption of this program via MBNL1 inhibition leads
to leukemia cell death. To test these hypotheses, our specific aims are 1) to determine the mechanism
underlying MLL-fusion leukemia dependence on MBNL1, and 2) optimize characteristics of a small-molecule
MBNL1 inhibitor as a treatment for MLL-fusion leukemia. To achieve the first aim, we will characterize changes
in key cell growth and death pathways which we hypothesize are responsible for the effects seen with genetic
knockdown. We will also identify novel MBNL1-mRNA interactions in MLL-fusion leukemia using CLIP-seq
(cross-linking immunoprecipitation with RNAseq). For the second aim, we have shown as a proof of concept
that a small molecule inhibitor of MBNL1 can induce MLL-fusion leukemia cell death. This compound requires
optimizations for potency, which we will achieve by applying medicinal chemistry principles. Furthermore, we
have used its structural characteristics and published crystal structures to initiate an in silico screen of a
proprietary compound library. This proposal will advance our understanding of the role of AS in the
pathogenesis of MLL-fusion leukemia, while also directly leading to a first-in-class therapy for this disease.
The applicant, who is currently an instructor in the Division of Oncology at Cincinnati Children’s Hospital
Medical Center, will execute this research plan while simultaneously engaging in structured didactics and
receiving close individual guidance from a panel of mentors as described in the application. These scientists
possess significant expertise in the molecular pathogenesis of leukemia. The experiments, mentoring, and
structured classwork described in this career development plan will position the applicant to successfully
transition into an independent researcher and physician-scientist, with expertise in the role of RNA binding
proteins in leukemia pathogenesis.
Terms: <0-11 years old><ALL1><ALL1 gene><AML - Acute Myeloid Leukemia><Acute Lymphoblastic Leukemia Protein 1><Acute Myeloblastic Leukemia><Acute Myelocytic Leukemia><Acute Myelogenous Leukemia><Alternate Splicing><Alternative RNA Splicing><Alternative Splicing><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Binding><Bone Marrow Grafting><Bone Marrow Transplant><Bone Marrow Transplantation><CXXC7><Cancer Treatment><Cancers><Cell Death><Cell Line><Cell Survival><Cell Viability><CellLine><Cellular Expansion><Cellular Growth><Characteristics><Child><Child Youth><Children (0-21)><Children's Hospital><Clinical><Complex><Cytotoxic Chemotherapy><Cytotoxic Therapy><DNA Rearrangement><Dependence><Development Plans><Disease><Disorder><Docking><Drosophila Homolog of Trithorax><Eukaryota><Eukaryote><Family><Family Therapy><Family psychotherapy><Gene Expression><Gene Rearrangement><Gene Transcription><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Goals><HRX><Hematopoietic><Immune Precipitation><Immunoprecipitation><Impairment><In Vitro><Individual><Infant><Infant Leukemia><Investigators><KMT2A><Laboratories><Lead><Leukemic Cell><Libraries><Lysine-Specific Methyltransferase 2A><MLL gene><MLL leukemia><MLL rearranged><MLL rearrangement><MLL-rearranged leukemia><MLL1><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Marrow Transplantation><Mediating><Medical center><Medicinal Chemistry><Mentors><Messenger RNA><Mixed Lineage Leukemia Gene><Mixed-Lineage Leukemia><Mixed-Lineage Leukemia Protein><Modality><Modernization><Molecular><Molecular Interaction><Multiple lineage leukemia 1><Mutation><Myeloid-Lymphoid Leukemia Gene><Myeloid-Lymphoid Leukemia Protein><Myeloid/Lymphoid Leukemia Gene><Myeloid/Lymphoid Or Mixed Lineage Leukemia Protein><Myeloid/Lymphoid or Mixed Lineage Leukemia Gene><Oncogenic><Oncology><Oncology Cancer><Outcome><Pathogenesis><Pathway interactions><Patients><Pattern><Pb element><Pediatric Hospitals><Pharmaceutic Chemistry><Pharmaceutical Chemistry><Physicians><Physiologic><Physiological><Position><Positioning Attribute><Pre-mRNA><Predisposition><Progenitor Cell Transplantation><Prognosis><Proteins><Proto Oncogene Proteins MLL><Publishing><RNA Expression><RNA Seq><RNA Splicing><RNA sequencing><RNA, Messenger, Precursors><RNA-Binding Proteins><RNAseq><Research><Research Personnel><Researchers><Role><Scientist><Secondary acute myeloid leukemia><Spliceosomes><Splicing><Stem Cell Transplantation><Stem cell transplant><Strains Cell Lines><Structure><Subgroup><Susceptibility><Testing><Therapy-Related Acute Myeloid Leukemia><Transcription><Treatment-Related AML><Treatment-Related Acute Myelocytic Leukemia><Treatment-Related Acute Myelogenous Leukemia><Treatment-related Acute Myeloid Leukemia><Work><Zinc Finger Protein HRX><acute granulocytic leukemia><acute myeloid leukemia><anti-cancer therapy><cancer therapy><cancer-directed therapy><career development><cell growth><chemotherapy><clinical care><crosslink><cultured cell line><effective therapy><effective treatment><efficacy validation><experiment><experimental research><experimental study><experiments><genome mutation><heavy metal Pb><heavy metal lead><hemopoietic><high risk group><high risk individual><high risk people><high risk population><improved><improved outcome><in silico><in vivo><infancy><infant acute leukemia><infantile><inhibitor><instructor><kids><knock-down><knockdown><leukemia><leukemogenesis><mRNA><mRNA Precursor><malignancy><member><necrocytosis><neoplasm/cancer><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><new treatment approach><new treatment strategy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><pathway><patient subclass><patient subcluster><patient subgroups><patient subpopulations><patient subsets><patient subtypes><pediatric acute leukemia><pharmacologic><progenitor><progenitor transplantation><programs><rational design><response><sAML><secondary AML><small molecular inhibitor><small molecule><small molecule inhibitor><social role><stem><stem and progenitor cell transplantations><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><transcriptome sequencing><transcriptomic sequencing><translational impact><validate efficacy><youngster>