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11.1 Acute myeloid leukaemia and related precursor neoplasms; myeloproliferative neoplasms; myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1; myelodysplastic/myeloproliferative neoplasms; myelodysplastic syndromes; acute leukaemias of ambiguous lineage; histiocytic and dendritic cell neoplasms.
11.2 In the case of t(15;17), t(8;21), t(16;16) or inv(16) whereby the presence of any of these cytogenetic abnormalities indicates acute myeloid leukaemia irrespective of blast percentage.
11.3 t(8;21)(q22;q22); inv(16)(p13.1;q22); t(16;16)(p13.1;q22); t(15;17)(q22;q12); t(9;11)(p22;q23); t(6;9)(p23;q34);
inv(3)(q21;q26.2); t(3;3)(q21;q26.2); t(1;22)(p13;q13).
11.4 In addition to acute myeloid leukaemia with BCR-ABL1, chronic myeloid leukaemia, BCR-ABL1 positive and B-lymphoblastic leukaemia/lymphoma with t(9;22)(q34.1;q11.2); BCR–ABL1.
11.5 This translocation fuses the promyelocytic leukaemia gene (PML) with the gene encoding the retinoic acid receptor alpha subunit (RARA). The fusion product PML-RARa has the ability to bind its native binding site, controlling the expression of retinoic acid inducible genes, but causes inhibition of these genes due to recruitment of powerful transcriptional repressors. Retinoic acid is required for maturation of myeloid cells beyond the promyelocyte stage, but recruitment of transcriptional repressors results in a maturational arrest at the promyelocyte stage in cells expressing PML-RARa.
11.6 Dysplastic features of granulocytes may include hypogranulated neutrophils, nuclear hypolobulation, and the presence of Auer rods. Red cell precursors may show vacuolization, multinuclearity, nuclear budding, and karyorrhexis. Platelet precursors may show multinuclearity, a hypolobulated nucleus, or micromegakaryocytes.
11.7 Therapies associated with the development of discrete secondary leukaemias include alkylating agents, ionizing radiation, and topoisomerase II inhibitors. These drugs all work by causing DNA damage. The principle behind their use is simple, they cause widespread DNA damage which should be detected by tumour suppressor proteins, inducing cell cycle arrest and activating apoptosis. Cross-linking of DNA, double-stranded DNA breaks, and the introduction of point mutations are all mechanisms through which these therapies can induce secondary leukaemias. Topoisomerase II inhibitors are associated with the development of leukaemias harbouring 11q23 abnormalities.
11.8 The GATA1 gene encodes a haemopoietic transcription factor that is disrupted in some cases of Down Syndrome (DS) leading to the production of a truncated transcription factor. GATA1 mutation is the ‘second hit’ in DS, which follows the initial trisomy 21. Combined, these hits result in Transient myeloproliferative disease and DS-AMKL.
11.9 Myeloproliferative neoplasms include PV, ET, and MF, and all have the capacity to transform into one another and into acute leukaemia. The key similarity between each of these subtypes is the presence of V617F point mutation in the JAK2 non-receptor tyrosine kinase. Approximately 90% of cases of PV, 50% MF, and 30% ET harbour this mutation. A range of other myeloproliferative neoplasms are also found, but these do not transform into one another.
11.10 Chronic myeloid leukaemia is a triphasic neoplasm comprising chronic and accelerated phases, terminating in blast crisis. The majority of patients present in chronic phase, which lasts for between 2 and 7 years. There is a high white cell count, but very few other clinical features except splenomegaly or hepatosplenomegaly. BCR–ABL1 will be present. Accelerated phase is associated with an increase in the number of immature cells circulating, and the basophil count will start to increase >20% total WBC. The leucocytosis will be difficult to control and patients may show thrombocythaemia or thrombocytopenia. Additional molecular or cytogenetic abnormalities may be detected. Blast crisis is an acute leukaemia. Blasts exceed 20%, and the patient’s prognosis is poor.