Acute myeloid leukemia (AML) is one of the most common hematopoietic malignancies, with NPM1 mutations and FLT3/ITDs being two of the most prognostic biomarkers for this disease. Patients with the NPM1Pos/FLT3-ITDNeg genotype account for approximately 25% of de novo AML cases and are currently classified as better-risk. However, approximately 40% of these patients do not obtain a remission or relapse within 2 years. We hypothesize that AML blasts with the NPM1Pos/FLT3-ITDNeg genotype harbor additional prognostic biomarkers that can be used to more accurately risk-stratify patients with this genotype. Therefore, we will examine viable leukemic blasts from AML patients with this genotype to identify novel genomic, transcriptional and proteomic prognostic biomarkers. We will then develop risk-stratification models incorporating these biomarkers and other prognostic factors and validate these risk-stratification models in an independent population of patients.
Specific Aim 1. Identify novel molecular biomarkers associated with prognosis in AML patients with the NPM1Pos/FLT3-ITDNeg genotype. Viable AML blasts will be isolated from patients with intermediate-risk cytogenetics and the NPM1Pos/FLT3-ITDNeg genotype (N=131). Targeted DNA sequencing, global RNA sequencing, and mass spectrometry employing an innovative approach will be used to identify DNA, transcript, and protein biomarkers that are associated with clinical outcomes. Regression analyses, integrating molecular data and other prognostic factors, will be used to identify the most informative biomarkers, and these prognostic biomarkers will be incorporated into risk-stratification models for estimating the probability of overall survival and relapse-free survival.
Specific Aim 2. Validate the ability of the biomarkers from Specific Aim 1 to more accurately risk-stratify AML patients with the NPM1Pos/FLT3-ITDNeg genotype. Targeted assays for biomarkers in the risk- stratification models will be developed. The design specifics of these assays will depend upon the characteristics of the target and rely upon previously developed and optimized technology. We will then examine the biomarkers and risk-stratification models in an independent population of AML patients with this genotype (N = 194). The performance of the risk-stratification model(s) employing will be evaluated by estimating AUCs and c-statistics. The results from this proposal will likely lead to the development of improved risk-stratification model(s) for AML patients with the NPM1Pos/FLT3-ITDNeg genotype. In addition, identified biomarkers may have prognostic significance beyond this genotype, and future studies will examine the generalizability of these findings to other AML subpopulations. Furthermore, the comprehensive nature of these studies, spanning from the genome to the proteome, will advance our understanding of the complex interactions among prognostic biomarkers, leading to more informed and potentially directive approaches for future biomarker research.

Public Health Relevance

Patients with acute myeloid leukemia (AML) frequently relapse after therapy. The proposed studies will identify methods to dramatically improve our ability to estimate the potential responses to therapy and lead to more targeted approaches for treating patients with this disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA190661-01A1
Application #
9105139
Study Section
Cancer Biomarkers Study Section (CBSS)
Program Officer
Agrawal, Lokesh
Project Start
2016-04-01
Project End
2021-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109