Acute Leukaemia

• haematopoiesis is the process of blood cell production and maturation beginning with haematopoietic stem cells which are self-renewal cells and can develop into any of the mature cells
• haematological malignancies are blood cancers such as leukaemia lymphoma or myeloma and can be acute or chronic
• the dysregulation of haematopoiesis causes an increase in cellular proliferation rate and a loss of apoptotic control
• leukaemia is the presence of malignant haematopoietic cells in the peripheral blood or bone marrow (can be acute or chronic)
• there are 4 main groups of haematological malignancies

  1. acute myeloid leukaemia (AML) - red blood cells
  2. acute lymphoblastic leukaemia (ALL) - white blood cells
  3. chronic myeloid leukaemia (CML)
  4. chronic lymphoblastic leukaemia (CLL)
• acute leukaemia is an accumulation of immature cells starting with the presence of blasts and then maturation arrest - it is aggressive and death occurs relatively rapidly
• the consequence of the loss of a cellular control mechanism within clonal progression is the acquisition of mutations within a cell
• the mutations within a cell during clonal progression occur at pro-onco genes which are activated to oncogenes with a gain-of-function mutation, however their normal function it cell growth and gene transcription
• tumor-suppressor genes help to prevent cell growth and cell proliferation and a loss-of-function mutation will cause the loss of a cellular control mechanism
• the patient's inheritance can be affected by the loss of cellular control mechanisms and can cause the development of trisomy 21, Fanconi syndrome and Diamond-Blackfan anaemia as well as an increased risk of developing AML
• environmental causes such as ionizing radiation, non-ionizing radiation, and chemicals such as benzene can occur due to the loss of cellular control mechanisms
• exposure to a known mutagen to induce DNA damage, radiotherapy and chemotherapy are all late effects of therapy and is a consequence to the loss of a cellular control mechanism
• infectious agents such as Epstein-Barr virus, human herpesvirus, and human T-lymphotropic virus can occur due to the loss of cellular control mechanisms within the cells
• scientists must be able to recognize each neoplastic disease including origin, clinical behaviour, morphology, cytogenic profile, and molecular makeup to form a standardized diagnostic framework
• recognition of neoplastic disease can occur through full/blood count, blood smear analysis, bone marrow smear analysis, cytogenetics analysis and genetic analysis
• different cancers respond to therapeutic agents differently
• accurate classification ensures patients are prescribed the appropriate medication and allows researchers to investigate and report diseases
• the main classification systems of leukaemia are the FAB system and the WHO system (acute vs chronic and myeloid vs lymphoid)
• according to the FAB classification, there are:

  • 8 subtypes of acute myeloid leukaemia (AML) - noted M0 to M7
  • 3 subtypes of acute lymphocytic leukaemia (ALL) - noted L1 to L3
• M0= undifferentiated acute myeloblastic leukaemia
• M1 - Acute myeloblastic leukaemia with minimal maturation
• M2 = Acute myeloblastic leukaemia with maturation
• M3 - acute promyelocytic leukaemia (APL_
• M4 = acute myelomonocytic leukaemia
• M4 eos = acute myelomonocytic leukaemia with eosinophilia
• M5 = acute monocytic leukaemia
• M6 = acute erythroid leukaemia
• M7 = acute megakaryoblastic leukaemia
• subtype of AML M0 through M5 all start in immature forms of white blood cells, M6 starts in very immature forms of red blood cells while M7 AML starts in immature forms of cells that make platelets
• the most common form of acute leukaemia in adults is acute myeloid leukaemia (AML) with 85-90% of cases, but only a minor fraction of cases in childhood at 10-15%
• clinical features of acute myeloid leukaemia include:

  • bone marrow failure
  • frequent infections
  • anaemia
  • thrombocytopenia (deficiency of platelets within the blood)
• laboratory findings of acute myeloid leukaemia include:

  • normochromic normocytic anaemia with thrombocytopenia
  • presence of blast cells (was more than or equal to 20%)
  • varied total EBC count
• AML WHO classifications:

  1. AML with recurrent genetic abnormalities
  2. AML with myelodysplasia-related changes (blasts >20%)
  3. Therapy-related myeloid neoplasms (t-AML)
  4. AML, not otherwise specified
  5. myeloid sarcoma
  6. myeloid proliferation related to down syndrome
  7. blastic plasmacytoid dendritic cell neoplasm
• AML with recurrent genetic abnormalities with specific gene mutations or chromosomal translocations - classification is mainly based on primary cytogenetic aberrations
• according to WHO there are 7 types of AML with chromosomal translocations caused by fusion proteins and 4 types of AML with gene mutations
• acute promyelocytic leukaemia with PML-RARA is associated with the translocation of the promyelocytic leukaemia gene (PML) with the RARA gene and occurs in 98% of patients with acute promyelocytic leukaemia causing the promyelocyte to not be fully developed
• PML encodes a multimeric protein necessary for assembling macromolecular PML nuclear bodies involved in self-renewal, DNA repair and apoptosis
• RARA encodes a nuclear receptor and ligand-dependent transcription factors
• the fusion of PML and RARA genes inhibits the actions of retinoic acid-responsive genes as well as inhibiting the granulocytic maturation and halt at the promyelocyte stage
• often patients with acute promyelocytic leukaemia with PML-RARA have a good prognosis