AML | Anatomy2Medicine
AML Leukemia

AML

 

  • Acute Myeloid Leukemia
      • a tumor of hematopoietic progenitors
      • caused by acquired oncogenic mutations that impede differentiation, leading to the accumulation of immature myeloid blasts in the marrow.
      • The arrest in myeloid development leads to marrow failure
      • AML peaks after 60 years of age
  • Classification.
      • AML WITH GENETIC ABERRATIONS
        • AML with t(8;21)(q22;q22); CBFα/ETO fusion gene (MCQ)
  • Favorable prognosis
          • FAB –M2 (MCQ)
          • Full range of myelocytic maturation
          • Auer rods easily found (MCQ)
          • abnormal cytoplasmic granules
        • AML with inv(16)(p13;q22); CBFβ/MYH11 fusion gene (MCQ)
          • Favorable prognosis
          • M4eo
          • Myelocytic and monocytic differentiation
          • abnormal eosinophilic precursors with abnormal basophilic granules (MCQ)
        • AML with t(15;17)(q22;11-12); RARα/PML fusion gene(MCQ)
          • Intermediate prognosis
  • M3, M3v
          • Numerous Auer rods, often in bundles within individual progranulocytes (MCQ)
          • primary granules usually very prominent in M3 subtype
          • high incidence of DIC (MCQ)
        • AML with t(11q23;v); diverse MLL fusion genes
          • Poor prognosis
  • M4, M5
        • AML with normal cytogenetics and mutated NPM
          • Favorable  prognosis
      • AML WITH MDS-LIKE FEATURES
  • With prior MDS
  • Poor prognosis
    • AML with multilineage dysplasia
  • Poor prognosis
        • AML with MDS-like cytogenetic aberrations
  • Poor prognosis
  • Associated with 5q-, 7q-, 20q-aberrations (MCQ)
      • AML, THERAPY-RELATED
        • Very poor prognosis
        • If following alkylator therapy or radiation therapy
          • 2- to 8-year latency period
          • MDS-like cytogenetic aberrations (e.g., 5q-, 7q-) (MCQ)
        • if following topoisomerase II inhibitor (e.g., etoposide) therapy,
          • 1 to 3-year latency
          • translocations involving MLL (11q23)
      • AML, NOT OTHERWISE SPECIFIED
        • AML, minimally differentiated – M0
        • AML without maturation – M1
        • AML with myelocytic maturation- M2
        • AML with myelomonocytic maturation- M4
        • AML with monocytic maturation -M5a, M5b
        • AML with erythroid maturation -M6a, M6b
        • AML with megakaryocytic maturation- M7
  • most common AML in Down syndrome (MCQ)
  • often accompanied by marrow fibrosis(MCQ)
  • Morphology.
        • The diagnosis of AML is based on the presence of at least 20% myeloid blasts in the bone marrow
        • Myeloblasts
          • have delicate nuclear chromatin
          • two to four nucleoli
          • more voluminous cytoplasm than lymphoblasts
          • The cytoplasm often contains fine, peroxidase-positive azurophilic granules. (MCQ)
          • Auer rods, are present in many cases(MCQ)
          • distinctive needle-like azurophilic granules, (MCQ)
          • they are particularly numerous in AML with the t(15;17) (acute promyelocytic leukemia) (MCQ)
        • Monoblasts
          • have folded or lobulated nuclei
          • lack Auer rods
          • are nonspecific esterase-positive(MCQ)
        • Why is a bone marrow examination is essential in pancytopenic patients ? (MCQ)
          • to exclude acute leukemia
          • Occasionally, blasts are entirely absent from the blood (aleukemic leukemia).
      • Cytogenetics.
        • Cytogenetic analysis has a central role in the classification of AML.
        • AMLs arising de novo in younger adults
          • commonly associated with balanced chromosomal translocations, particularly t(8;21), inv(16), and t(15;17) (MCQ)
        • AMLs following MDS or exposure to DNA-damaging agents (such as chemotherapy or radiation therapy)
          • often have deletions or monosomies involving chromosomes 5 and 7 (MCQ)
          • usually lack chromosomal translocations.
          • The exception to this rule is AML occurring after treatment with topoisomerase II inhibitors, which is strongly associated with translocations involving the MLL gene on chromosome 11q23.
        • AML in the elderly
          • more likely to be associated with “bad” aberrations, such as deletions of chromosomes 5q and 7q. (MCQ)
      • Molecular Pathogenesis.
  • Many recurrent genetic aberrations seen in AML disrupt genes encoding transcription factors that are required for normal myeloid differentiation.
  • t(8;21) and inv(16), (MCQ)
            • disrupt the CBF1α and CBF1β genes, respectively.
            • CBF1α and CBF1β genes encode polypeptides that bind one another to form a CBF1α/CBF1β transcription factor that is required for normal hematopoiesis.
  • t(8;21) and the inv(16) (MCQ)
            • create chimeric genes encoding fusion proteins that interfere with the function of CBF1α/CBF1β
            • block the maturation of myeloid cells
            • mutated tyrosine kinases collaborate with transcription factor aberrations to produce AML.
  • AML with the t(15;17), acute promyelocytic leukemia(MCQ)
            • t(15;17) creates yet another fusion gene that encodes a part of the retinoic acid receptor-α (RARα) fused to a portion of a protein called PML (after the tumor). (MCQ)
            • What is normal RARα function ?
              • In the presence of physiologic amounts of retinoic acid, normal RARα interacts with other transcription factors to activate genes that are needed for granulocytic differentiation
            • What happens with PML-RARα fusion protein ? (MCQ)
              • However, the PML-RARα fusion protein interacts instead with transcriptional repressors, which results in an inhibition of granulocytic maturation
            • AMLs with the t(15;17) also have frequent activating mutations in FLT3(MCQ)
              • What is FLT3 ?
                • FLT3 is a receptor tyrosine kinase (MCQ)
                • It transmits signals that increase cellular proliferation and survival.
            • Why is aberrant tyrosine kinase activation is a common and universal feature of AML.
  • FLT3 mutations are found in Acute Promyelocytic (M3) type AML
  • FLT3 mutations are found in of AML associated with NPM (nucleophosmin) mutations
              • activating mutations in tyrosine kinase receptor, c-KIT, are found in about 25% of AMLs associated with the inv(16) or the t(8;21) (MCQ)
        • Tumors with t(15;17) translocation respond to pharmacologic doses of all-trans retinoic acid (ATRA) – Mechanism (MCQ)
          • ATRA binds to the PML-RARα fusion protein
          • antagonizes Inhibitory effect of PML-RARα fusion protein on the transcription of target genes.
  • Remarkably, the resulting activation of transcription overcomes the block in differentiation
          • within 1 to 2 days the neoplastic promyelocytes begin to differentiate into neutrophils, which rapidly die.
  • Clinical Features.
  • Most patients present within weeks or a few months due to pancytopenia
      • Procoagulants and fibrinolytic factors released by AML with the t(15;17), exacerbate the bleeding tendency(MCQ)
      • tumors with monocytic differentiation often infiltrate the skin (leukemia cutis) and the gingiva(MCQ)
      • CNS spread is less common than in ALL.
      • Myeloblastoma, Granulocytic sarcoma, or Chloroma.
        • AML presents as a localized soft-tissue mass
        • They inevitably progress to full-blown AML over time.
    • Prognosis.
      • AML is a difficult disease to treat.
      • AMLs with t(8;21) or inv(16) (MCQ)
        • have a relatively good prognosis with conventional chemotherapy, particularly in the absence of c-KIT mutations
      • prognosis is dismal for AMLs that (MCQ)
        • follow MDS or genotoxic therapy
        • occur in the elderly

AML with poor prognosis is treated with bone marrow transplantation when possible.