Acute myeloid leukemia pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2], Raviteja Guddeti, M.B.B.S. [3], Carlos A Lopez, M.D. [4], Shyam Patel [5]; Grammar Reviewer: Natalie Harpenau, B.S.[6]

Overview

Normal hematopoiesis involves the production of blood cells, and this normal physiologic process is dysregulated in acute myeloid leukemia. The pathophysiology of acute myeloid leukemia involves multiple mechanisms, including altered signal transduction and autonomous proliferation, differentiation blockade, evasion of apoptosis, and self-renewal. The pathophysiology of acute promyelocytic leukemia is most commonly due to a reciprocal translocation between chromosomes 15 and 17. The novel gene production causes a differentiation block in myeloid cells. There are multiple different binding partners for the RARA gene, so multiple translocations can contribute to the pathogenesis of acute promyelocytic leukemia.

Pathophysiology

In order to understand the pathophysiology of acute myeloid leukemia, it is important to understand normal physiology of hematopoiesis or blood cell production.

Normal Hematopoiesis

Pathophysiology of Acute Myeloid Leukemia

  • The malignant cell in acute myeloid leukemia is the myeloblast. However, in acute myeloid leukemia a single myeloblast accumulates genetic changes, which "freeze" the cell in its immature state and prevent differentiation.[3]
  • This type of mutation alone does not cause leukemia. However, when such a differentiation arrest is combined with other mutations, which disrupt genes controlling proliferation, the result is the uncontrolled growth of an immature clone of cells, leading to the clinical entity of acute myeloid leukemia.[4]
  • Much of the diversity and heterogeneity of acute myeloid leukemia stems from the fact that leukemic transformation can occur at a number of different steps along the differentiation pathway.[5]
  • Human acute myeloid leukemia is organized as a hierarchy, and the cancer stem cell hypothesis best models the pathophysiology of acute myeloid leukemia.
  • Modern classification schemes for acute myeloid leukemia recognize that the characteristics and behavior of the leukemic cell (and the leukemia) may depend on the stage at which differentiation was halted.

Role of Altered Signal Transduction and Autonomous Proliferation (Protein Tyrosine Kinase Activation)

Role of Altered Gene Expression and Differentiation Blockade

Evasion of Apoptosis (Protein Tyrosine Kinase Activation)

  • The increased expression of Bcl-2 pro-survival molecule plays a key role in evasion of programmed cell death in AML.[21]
  • PI 3-kinase activates the AKT serine/threonine kinase, and this kinase in turn phosphorylates BAD and releases the BCL-2 anti-apoptotic molecule.[22][23]
  • The RUNX1-MTG8 fusion protein of AML represses the expression of p14ARF and promotes destabilization of p53 (a tumor suppressor gene).[24][25][26]

Self-Renewal

  • The myeloid cells in acute myeolid leukemia have an ability to self-renew without being committed to a specific cell lineage.[27]
  • The self-renewing capacity of myeloid cells in AMLs is thought to be mediated by the following:
    • Fusion of ALK tyrosine kinase with nucleophosmin protein (NPM)[28]
    • Mutation of FLT3-ITD[29][30]
    • RUNX1-MTG8, PML-RARα, and PLZF-RARα fusions can all induce the expression of β-catenin and γ-catenin (plako-globin) proteins[31][32]
    • The Wnt signalling pathway has also been shown to be involved in self-renewal of myeloid cells[33]

Pathophysiology of Acute Promyelocytic Leukemia

  • The pathophysiology of acute promyelocytic leukemia begins with a balanced reciprocal chromosomal translocation in hematopoietic stem cells.
  • The chromosomal translocation involves the juxtaposition of the retinoic acid receptor-alpha gene (RARA) on the long arm of chromosome 17 with another gene (most commonly the promyelocytic leukemia gene (PML) on the long arm of chromosome 15).[34]
  • The translocation is designated as t(15;17)(q22;q12). The PML-RARA fusion product is a transcriptional regulator and binds to retinoic acid response elements in the promoter regions of the genome. The PML-RARA fusion product serves to recruit co-repressors of gene transcription, preventing myeloid differentiation.[35]
  • This is known as a differentiation block, since the cells are unable to differentiate into normal mature cells.
  • The cells remain primitive and stem-like, which is the basis for the malignancy.
  • The result of the chromosomal translocation is ineffective blood cell production and uncontrolled proliferation of malignant promyelocytes.[34]
  • In 95% of cases of acute promyelocytic leukemia, the translocation involved PML and RARA. However, it is important to note that RARA has multiple other binding partners which can lead to the development or acute promyelocytic leukemia, as shown in the table below.
Translocation Partner Chromosomal Location Function Response to Therapy Other Features

PML

15q24.1

  • A member of the tripartite motif (TRIM) family
  • Localizes to nucleolar bodies and functions as a transcription factor and tumor suppressor
  • Regulate p53 response to oncogenic growth signals
  • Influenced by the cell cycle
  • Sensitive to all-trans retinoic acid[36]
  • Most common translocation
  • Found in 70-90% of cases[37]

PLZF (ZBTB16)[34][37]

11q23.2

  • Encodes a zinc finger transcription factor
  • Involved in cell cycle regulation
  • Interacts with histone deacetylases
  • Resistant to all-trans retinoic acid[36]
  • Second most common translocation (after PML-RARA)

NPM1

5q35.1

  • Encodes nucleophosmin 1 (a nucleolar shuttle protein)
  • Involved in centromere duplication
  • Serves a protein chaperone
  • Regulates the cell cycle
  • Sequesters the tumor suppressor ARF in the nucleus and protects ARF from degradation
  • Sensitive to all-trans retinoic acid[36]

NUMA[36]

11q13.4

  • Contributes to a structural component of the nuclear matrix
  • Interacts with microtubules
  • Contributes to mitotic spindle formation during cell division
  • Sensitive to all-trans retinoic acid[36]
  • Rare translocation

STAT5B[37]

17q21.2

  • Encodes a signal transducer and activator of transcription (STAT)
  • Serves an intracellular transduction molecule for cytokine signaling
  • Translocates to the nucleus and functions as a transcription factor
  • Involved in T cell receptor signaling
  • Involved in apoptosis
  • Sequesters the tumor suppressor ARF in the nucleus and protects ARF from degradation
  • Resistant to all-trans retinoic acid[36]
  • Rare translocation

Microscopic Pathology

Description of pictures (shown below) according the classification of Acute myeloid leukemia system.

Acute myeloid leukemia- M0 classification

  • Acute myeloid leukemia M0 with lack of obvious myeloid differentiation by routine histologic examination and presence of myeloperoxidase in <3% of blasts
  • Morphologically, blasts are small to large with no granules or Auer rods
Acute myeloid leukemia-M0 - lack of obvious myeloid differentiation by routine histologic examination and presence of myeloperoxidase in <3% of blasts. Morphologically, blasts are small to large with no granules or Auer rods. Images shown are courtesy of Melih Aktan MD., Istanbul Medical Faculty - Turkey, and Kyoto University - Japan


Acute myeloid leukemia- M1 classification

  • Presence of more than 90% myeloblasts in blood
  • Peroxidase
Images shown below are courtesy of Melih Aktan MD., Istanbul Medical Faculty - Turkey, and Kyoto University - Japan


Acute myeloid leukemia- M2 classification

  • Presence of granules can be noted
  • Large myeloblasts with prominent nucleoli
Images shown below are courtesy of Melih Aktan MD., Istanbul Medical Faculty - Turkey, and Kyoto University - Japan AML-M2 - large myeloblasts with prominent nucleoli.


Acute myeloid leukemia- M3 classification

  • Also known as promyelocytic leukemia
  • Hypergranular morphology with most cells containing abundant large granules
  • Ruptured cells are releasing their granules free onto the slide
  • Presence of Auer rods can be noticed
Images shown below are courtesy of Melih Aktan MD., Istanbul Medical Faculty - Turkey, and Kyoto University - Japan. AML-M3 - polarity of cytoplasmic granulation. In many cells the granules tend to polarize toward one portion of the cytoplasm and the nucleus on the opposite side.


Acute myeloid leukemia- M5a and M5b classification

  • M5a: >80% monoblasts in the marrow
  • M5a: large monoblasts with fine nuclear chromatin and prominent nucleoli (note the absence of Auer rods)
  • M5b: <80% monoblasts in the marrow
Images shown below are courtesy of Melih Aktan MD., Istanbul Medical Faculty - Turkey, and Kyoto University - Japan. M5b: <80% monoblasts in the marrow
Images shown below are courtesy of Melih Aktan MD., Istanbul Medical Faculty - Turkey, and Kyoto University - Japan. M5a: >80% monoblasts in the marrow


Acute myeloid leukemia- M7 classification

  • Irregular cytoplasmic border is often noted in some of the megakaryoblasts and occasionally projections resembling budding atypical platelets are present
    • Megakaryoblasts are usually medium-sized to large cells with a high nuclear-cytoplasmic ratio
    • Nuclear chromatin is dense and homogeneous
    • Variable basophilic cytoplasm which may be vacuolated
    • An irregular cytoplasmic border is often noted in some of the megakaryoblasts and occasionally projections resembling budding atypical platelets are present
    • Megakaryoblasts lack myeloperoxidase (MPO) activity and stain negatively with Sudan black B
    • Clumps or granules in the cytoplasm
    • PAS staining varies from negative to focal or granular positivity, to strongly positive staining
    • More precise identification is by immunophenotyping or with electron microscopy (EM)
    • Immunophenotyping using MoAb to megakaryocytic restricted antigen (CD41 and CD61) may be diagnostic
Images shown below are courtesy of Melih Aktan MD., Istanbul Medical Faculty - Turkey, and Kyoto University - JapanAML-M7 - irregular cytoplasmic border is often noted in some of the megakaryoblasts and occasionally projections resembling budding atypical platelets are present.


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