Presenter Status
Student
Abstract Type
Research
Primary Mentor
Midhat Farooqi, MD, PhD
Start Date
14-5-2025 11:30 AM
End Date
14-5-2025 1:30 PM
Presentation Type
Poster Presentation
Description
Objectives/Goals
Acute Myeloid Leukemia (AML) is the second most common leukemia among pediatric populations. Approximately 15% of pediatric AML cases have KMT2A gene rearrangements (KMT2A-r), which carry a worse prognosis. Our goal is to better characterize the biologic landscape of KMT2A-r pediatric AML. We hypothesize that a multi-omic approach will reveal mechanisms underlying the aggressive nature of KMT2A-r AML.
Methods/Study Population
This study makes use of deidentified peripheral blood and/or bone marrow samples banked in the Children’s Mercy Tumor Bank Biorepository. For this study, we used samples at diagnosis and remission from four KMT2A-r pediatric AML patients, six patients with other AML subtypes, and 47 patients with other leukemia subtypes. We performed differential expression (DE) analysis on bulk and single-cell RNA sequencing comparing KMT2A-r and all other AML subtypes. We performed proteomic analysis on samples from 4 patients with KMT2A-r AML, with samples taken at diagnosis, remission prior to bone marrow transplant, and remission following bone marrow transplant. We then coalesce these data to better identify processes and pathways that are dysregulated in KMT2A-r AML.
Results/Discussion
Transcriptomic analysis showed HOXA10 and MEIS1, two genes associated with immature myeloid populations and KMT2A-r leukemias, were more highly transcribed in AMLs than other leukemias. Our DE analysis showed significantly higher transcription of ITGA7, a gene shown to correlate with poorer prognosis in AML, in our KMT2A-r samples. FAM46C, a tumor suppressor gene contributing to mRNA stabilization, was less highly expressed in KMT2A-r AML when compared to other AML subtypes. Low expression of FAM46C is strongly associated with poorer survival and treatment response in multiple myeloma, but our findings suggest it may also be relevant to AML.
Proteomic analysis demonstrated TDP2 was more highly expressed in KMT2A-r AML diagnosis samples than at remission. TDP2 has been shown to play a role in RNA-DNA damage response and act as an oncogenic factor via activation of the MAPK-ERK pathway. This analysis also demonstrated higher expression of HMG20B at diagnosis. HMG20B has been shown to play an important role in the leukemia cell differentiation block characteristic of AML.
Taken in combination, these results provide new hypotheses for the mechanisms contributing to this aggressive leukemia subtype and provide potential new targets for treatment.
Included in
Higher Education and Teaching Commons, Medical Education Commons, Pediatrics Commons, Science and Mathematics Education Commons
Multi-omic Analysis of KMT2A-rearranged Pediatric Acute Myeloid Leukemia Reveals Novel Pathways of Interest
Objectives/Goals
Acute Myeloid Leukemia (AML) is the second most common leukemia among pediatric populations. Approximately 15% of pediatric AML cases have KMT2A gene rearrangements (KMT2A-r), which carry a worse prognosis. Our goal is to better characterize the biologic landscape of KMT2A-r pediatric AML. We hypothesize that a multi-omic approach will reveal mechanisms underlying the aggressive nature of KMT2A-r AML.
Methods/Study Population
This study makes use of deidentified peripheral blood and/or bone marrow samples banked in the Children’s Mercy Tumor Bank Biorepository. For this study, we used samples at diagnosis and remission from four KMT2A-r pediatric AML patients, six patients with other AML subtypes, and 47 patients with other leukemia subtypes. We performed differential expression (DE) analysis on bulk and single-cell RNA sequencing comparing KMT2A-r and all other AML subtypes. We performed proteomic analysis on samples from 4 patients with KMT2A-r AML, with samples taken at diagnosis, remission prior to bone marrow transplant, and remission following bone marrow transplant. We then coalesce these data to better identify processes and pathways that are dysregulated in KMT2A-r AML.
Results/Discussion
Transcriptomic analysis showed HOXA10 and MEIS1, two genes associated with immature myeloid populations and KMT2A-r leukemias, were more highly transcribed in AMLs than other leukemias. Our DE analysis showed significantly higher transcription of ITGA7, a gene shown to correlate with poorer prognosis in AML, in our KMT2A-r samples. FAM46C, a tumor suppressor gene contributing to mRNA stabilization, was less highly expressed in KMT2A-r AML when compared to other AML subtypes. Low expression of FAM46C is strongly associated with poorer survival and treatment response in multiple myeloma, but our findings suggest it may also be relevant to AML.
Proteomic analysis demonstrated TDP2 was more highly expressed in KMT2A-r AML diagnosis samples than at remission. TDP2 has been shown to play a role in RNA-DNA damage response and act as an oncogenic factor via activation of the MAPK-ERK pathway. This analysis also demonstrated higher expression of HMG20B at diagnosis. HMG20B has been shown to play an important role in the leukemia cell differentiation block characteristic of AML.
Taken in combination, these results provide new hypotheses for the mechanisms contributing to this aggressive leukemia subtype and provide potential new targets for treatment.
