by Matthew A. Held, Ph.D.
Tue, Dec 16th, 2025 3:11 pm
Understanding the molecular drivers of acute myeloid leukemia (AML) has transformed how clinicians diagnose, classify, and treat this complex disease. Two of the most informative genetic alterations—NPM1 mutations and the PML-RARA translocation—play a central role in defining AML subtypes, guiding therapy decisions, and predicting patient outcomes.
In this blog, we take a closer look at these key biomarkers: how common they are, what they mean for disease biology, and why identifying them through molecular testing has become standard practice in modern hematology-oncology. Whether you're involved in laboratory diagnostics, clinical decision-making, or simply interested in the science behind precision medicine, this overview provides a clear foundation for understanding their clinical significance.
NPM1 mutations are present in roughly one-third of all AML patients and in up to 60% of those with a normal karyotype. Among the various NPM1 mutations, the most common—Type A, Type B, and Type D—are four–base pair insertions in a region of the gene that normally directs the protein to the cell nucleus. These mutations cause the NPM1 protein to mislocalize to the cytoplasm, disrupting critical cellular processes such as genomic stability, regulation of cell growth, and normal blood cell differentiation. This loss of control can drive the unchecked proliferation of myeloid cells, ultimately contributing to leukemia development. Because of their clinical importance, detecting NPM1 mutations is now a standard part of AML diagnostic testing and helps guide treatment decisions, including whether patients receive conventional chemotherapy or newer targeted therapies. Importantly, NPM1 mutation together with FLT3-ITD status guides risk stratification and therapy under clinical guidelines (e.g. ELN and NCCN).
Certain subtypes of leukemia are driven by specific genetic alterations. One well-known example is Acute Promyelocytic Leukemia (APL), a subtype of AML that accounts for roughly 10–15% of adult cases. APL is characterized by a specific chromosomal translocation between the PML gene on chromosome 15 and the RARA gene on chromosome 17, resulting in the PML-RARA fusion. This fusion protein disrupts the normal function of the RARA receptor, which plays a key role in regulating the differentiation of promyelocytes into mature granulocytes. By blocking this differentiation process, the PML-RARA protein causes immature promyelocytes to accumulate, leading to uncontrolled cell proliferation and the development of leukemia. Unlike many forms of AML, APL has a favorable prognosis thanks to targeted therapies like all-trans retinoic acid (ATRA), which can restore proper differentiation. Combinatorial treatment (e.g. ATRA plus arsenic trioxide) can result in complete remission rates reaching 80–90% or higher.
Molecular testing is essential for guiding treatment in leukemia. Key assays include:
Detecting NPM1 mutations helps identify patients for targeted therapies, and regular use of external quality controls (EQCs) ensures reliable results.
These tests enable accurate diagnosis and timely treatment, improving remission rates and patient outcomes.
Together, these molecular assays are cornerstones of precision medicine, helping clinicians deliver the right treatment to the right patient.
By uncovering the key genetic drivers behind AML—NPM1 mutations and the PML-RARA translocation—clinicians can move beyond one-size-fits-all treatment. Molecular testing makes it possible to classify leukemia subtypes with precision, guide therapy choices, and improve patient outcomes. These assays are more than just diagnostic tools—they are the foundation of personalized medicine, ensuring that each patient receives the right treatment at the right time. As research and technology continue to advance, understanding and testing for these mutations will remain central to transforming AML care.
Since the summer of 2021, Matthew A. Held, Ph.D. has been a scientist in the R&D department at Maine Molecular Quality Controls, Inc. (MMQCI) in Saco, Maine. He has been a Lead Project Scientist on many different control products for various diagnostic applications including FDA and CE- cleared oncology and infectious disease clinical lab assays, and is responsible for the development of these products throughout their entire life-cycle, from design to market launch.
Dr. Held earned his PhD in Cell & Molecular Biology at the University of Vermont, Robert Larner College of Medicine in 2009 and attained further postdoctoral training at Yale Medical School and Massachusetts General Hospital before joining Maine Medical Research Institute and the University of New Hampshire as a staff scientist. His academic research spans over 15 years in the fields of solid tissue oncology, and hematological development.
Matthew A. Held, Ph.D.