Acute Myeloid Leukemia (AML) Pathogenesis

Normal Hematopoiesis1

In normal hematopoiesis, pluripotent hematopoietic stem cells (HSCs) give rise to all of the different types of blood cells. When a hematopoietic stem cell divides, one of the 2 daughter cells may remain a stem cell and the other may differentiate into a myeloid or lymphoid stem cell.1

  • Myeloid stem cells differentiate further into1:
    • Megakaryoblasts, which give rise to megakaryocytes and ultimately platelets
    • Proerythroblasts, which differentiate into red blood cells, or erythrocytes
    • Myeloblasts, which differentiate into basophils, neutrophils, or eosinophils
    • Monoblasts, which differentiate into monocytes
  • Lymphoid stem cells differentiate into lymphoblasts, which then further differentiate into1:
    • Natural killer cells
    • Small lymphocytes, which differentiate into B and T cells

Recent advances in genomics, HSC biology, and studies using in vivo models have helped scientists to understand more about the pathogenesis of AML, which is covered in the next section.2

AML Pathogenesis


  • AML is a heterogenous clonal disease that can arise from genetic and epigenetic alterations in hematopoietic stem cells and/or myeloid stem cells that disrupt the regulation of key events such as self-renewal, proliferation, and differentiation3
  • In AML, driver mutations such as DNMT3A (see figure) can occur in hematopoietic stem cells or myeloid stem cells3
  • Cooperating driver mutations, such as FLT3-ITD (see figure), then trigger the development of a fully transformed leukemic stem cell with unlimited self-renewal potential and impaired differentiation3
  • In about half of patients, chromosomal abnormalities are found by cytogenetic analysis, and are used for classification and prognostic risk stratification4,5

Abnormalities Associated With AML

Mutations associated with AML can occur on several levels:

  • Cytogenetic mutations involve chromosomal abnormalities, such as chromosomal duplications, deletions, and/or translocations6
  • Molecular mutations involve changes to the DNA sequence, including point mutations, insertions, and/or deletions6
  • Epigenetic changes alter gene expression through biochemical changes without altering the DNA sequence7

~25% of AML patients experience no further mutational gain at relapse.8

Image above created with BioRender.com

References: 1. Betts JG, Young KA, Wise JA, et al. Anatomy and Physiology. 2nd ed. Houston, TX: OpenStax, Rice University; 2017. https://openstax.org/details/books/anatomy-and-physiology. Accessed March 3, 2021. 2. Grove CS, Vassiliou GS. Acute myeloid leukaemia: a paradigm for the clonal evolution of cancer? Dis Model Mech. 2014;7(8):941-951. 3. Chan SM, Majeti R. Role of DNMT3A, TET2, and IDH1/2 mutations in pre-leukemic stem cells in acute myeloid leukemia. Int J Hematol. 2013;98(6):648-657. 4. Kumar CC. Genetic abnormalities and challenges in the treatment of acute myeloid leukemia. Genes Cancer. 2011;2(2):95-107. 5. Wan TS. Cancer cytogenetics: methodology revisited. Ann Lab Med. 2014;34(6):413-425. 6. Mahdieh N, Rabbani B. An overview of mutation detection methods in genetic disorders. Iran J Pediatr. 2013;23(4):375-388. 7. NCI Dictionaries: Epigenetics. National Cancer Institute website. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/epigenetics. Accessed March 3, 2021. 8. Vosberg S, Greif PA. Clonal evolution of acute myeloid leukemia from diagnosis to relapse. Genes Chromosomes Cancer. 2019;58(12):839-849.