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PA18.1-2 | Acute Leukaemias — AML & ALL — Part 1
CLINICAL SCENARIO
A 6-year-old boy is brought to the paediatric OPD with three weeks of fatigue, recurrent fever, and easy bruising. His mother noticed his gums bleeding while brushing. On examination: pallor, petechiae on both legs, cervical lymphadenopathy, and a firm spleen tip 3 cm below the costal margin. His CBC shows Hb 7.2 g/dL, TLC 85,000/µL, platelets 28,000/µL. The peripheral smear is peppered with large, primitive cells. What has shut down his bone marrow—and what do these cells tell you about the subtype?
WHY THIS MATTERS
Acute leukaemias account for roughly 30% of all childhood cancers and are the commonest life-threatening haematological malignancy in adults under 60. The distinction between AML and ALL is not academic—it determines whether the child gets a glucocorticoid-based protocol or an anthracycline-cytarabine regime. Pathologists and haematologists must reach this distinction within hours of a marrow aspirate. Understanding the pathological basis of that distinction is the core task of this module.
RECALL
Before proceeding, confirm you can answer these from Year-1:
• What is normal haematopoiesis? Which progenitor gives rise to myeloid vs lymphoid lineages?
• What are blasts? How do they differ from mature myeloid cells morphologically?
• What is the normal blast percentage in bone marrow?
• What does cytopaenia mean, and how do anaemia, neutropaenia, and thrombocytopaenia each manifest clinically?
If any of these feel uncertain, revisit your physiology notes before continuing.
What Is Leukaemia? Acute vs Chronic
Leukaemia: Acute versus Chronic
Leukaemia is a clonal malignant proliferation of haematopoietic progenitor cells that infiltrates the bone marrow, replaces normal haematopoiesis, and spills into the peripheral blood.
The acute–chronic distinction rests on blast percentage and clinical tempo:
| Feature | Acute | Chronic |
|---|---|---|
| Blast % (BM or PB) | ≥20% (WHO criterion) | <20% |
| Cell of origin | Early progenitor (blast) | More mature precursor |
| Onset | Abrupt (days–weeks) | Insidious (months–years) |
| Untreated course | Fatal within weeks | Months to years |
| Key mechanism | Maturation arrest | Excessive proliferation, some differentiation |
The 20% blast threshold replaced the older FAB 30% cut-off in the 2001 WHO classification. Certain cytogenetic findings (e.g., t(8;21), t(15;17), inv(16)) are diagnostic of AML regardless of blast count—a critical exception to remember.
Aetiology of Acute Leukaemias
Aetiology and Pathogenesis of Acute Leukaemias
Most acute leukaemias arise without a clearly identifiable cause, but several aetiological risk factors are established:
Radiation: Ionising radiation (atomic bomb survivors, therapeutic radiation) causes chromosomal breaks. Risk is dose-dependent and latency is 5–10 years.
Chemical exposure: Benzene (a myelotoxin) and occupational petroleum products increase AML risk. Alkylating chemotherapy agents (cyclophosphamide, melphalan) and topoisomerase II inhibitors (etoposide) cause therapy-related AML (t-AML), typically with complex karyotypes or 11q23 rearrangements.
Pre-existing haematological conditions: Myelodysplastic syndrome (MDS) transforms to AML in ~30% of cases (secondary AML). Myeloproliferative neoplasms (CML, PV) can undergo blast transformation.
Genetic syndromes:
• Down syndrome (trisomy 21): 10–20× increased AML risk; a transient myeloproliferative disorder in neonates may precede AML.
• Fanconi anaemia, Bloom syndrome, ataxia-telangiectasia: DNA repair defects predispose to AML.
• Li-Fraumeni syndrome (TP53 germline): elevated risk of ALL and AML.
Viruses: HTLV-1 causes adult T-cell leukaemia/lymphoma (ATL)—a distinct entity, not classic ALL.
Pathogenesis: Maturation Arrest and Clonal Expansion
Maturation Arrest and Clonal Expansion in Acute Leukaemia
The central concept in acute leukaemia pathogenesis is maturation arrest: a somatic mutation (or cooperating pair of mutations) freezes haematopoietic progenitors at an immature blast stage. These blasts retain the capacity for clonal proliferation but cannot complete differentiation.
The result: the marrow fills with non-functional blasts, leaving no room for normal erythroid, myeloid, and megakaryocytic precursors → marrow failure → anaemia + neutropaenia + thrombocytopaenia.
The two-hit model (proposed by Gilliland & Griffin) suggests cooperation between:
1. Class I mutations — activate proliferation/survival (e.g., FLT3-ITD, RAS, BCR-ABL)
2. Class II mutations — block differentiation (e.g., RUNX1-RUNX1T1 from t(8;21), PML-RARα from t(15;17), CEBPA mutations)
Neither class alone is sufficient; together they produce the full leukaemic phenotype. This framework explains why some cytogenetic lesions predict both prognosis and treatment response.
SELF-CHECK
A mutation that activates FLT3 (a receptor tyrosine kinase) without blocking differentiation would, according to the two-hit model, be:
A. Sufficient alone to cause AML
B. A Class I mutation requiring a cooperating Class II hit
C. A Class II mutation causing maturation arrest
D. Unrelated to leukaemogenesis
Reveal Answer
Answer: B. A Class I mutation requiring a cooperating Class II hit
FLT3-ITD is a Class I mutation — it drives proliferation and survival but does not block differentiation. A cooperating Class II mutation (e.g., RUNX1-RUNX1T1 blocking myeloid maturation) is needed to produce the full leukaemic phenotype. This is why FLT3-ITD alone in mice does not reliably cause AML.