BIOLOGY 2F03 Chapter 9-10: PROMYELOCYTIC LEUKAEMIA
20 May 2018
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ACUTE PROMYELOCYTIC LEUKAEMIA (APML)
1. Clinical features of Acute Promyelocytic Leukaemia
• Patients usually present with haemorrhage resulting from DIC
o Bleeding from venupuncture sitre
o Mucosal bleeding
o Low platelet count (platelets used up)
• The mean age of onset is about 40years old, DIC occurs within the first few weeks and can be
fatal
o Watch out for ganagrene, pulmonary and cerebral haemorrhages
o The pathophysiology is due to increased TF rexpression/release by the promyelocytes
and increased fibrinolysis (because of annexin 2)
• Patient may present with a low white cell count, and a higher white cell count is a bad
prognostic marker
2. There is no role for immunophenotyping in the diagnosis of APML
• Morphology - Blood film/ bone marrow aspirate
o M3 FAB AML - granular blasts where you can’t really see the nucleus
o Faggott cells may appear - they have an abundance of auer rods
o M3 variant has less granular/darkly staining cytoplasms - the nucleus may also appear
clefted
• Cytogenetics - FISH
o Karyotyping takes about a week - FISH is better because DIC might kill them before this
o Looking for characteristic t(15;17)(q22;q21) - PML-RARa
• Anti-PML antibody?
3. The roles of PML-RARa and outlines of treatment for APML
• Usually retinoic acid binds to RARa to unwind chromatin and activate transcription
• PML-RARa binds strongly to the repressor-complex and is resistant to physiological levels of RA.
o Less transcription = Block in differentiation at promyelocyte stage
o Continued prolioferation and failure of apoptosis
• ATRA is essentially a super-charged RA dose
o It induces differentiation into neutrophils
▪ Blast → PM → M →metaM → band cell → neutrophil
o It facilitates apoptosis
o The leukaemic clone is replaces by normal cells
• ATRA is usually used in combination with one cycle of anthracycline-based-chemotherapy. This
reduces DIC and thus haemorrhage-related-early-mortality
• Arsenic is emerging as another treatment
o it releases caspase III from mitochondria to facilitate apoptosis
o it degrades PMl-RARa without degrading normal RARa
o it may be of use in ATRA-resistant patients
1. the ATRA (/differentiation) syndrome is a side effect of ATRA treatment
• clinical features - SOB, oedema, weight gain, pulmonary infilitrates and hypoBP
o (can also occur with arsenic treatment)
• Believed to be related to rising numbers of differentiating myeloid cells
Document Summary
It induces differentiation into neutrophils: blast pm m metam band cell neutrophil. It facilitates apoptosis: the leukaemic clone is replaces by normal cells, atra is usually used in combination with one cycle of anthracycline-based-chemotherapy. 2. 17- pathobiology of multiple myeloma develops: functional ig rearrangement (vdj), somatic hypermutation and ig heavy-chain class (from igm to. Juxtaposition of igh with a gene promoter is found in 48% mgus, 73% of all mm and. Bcl -1 cyclin d1: nb a different breakpoint in the same 14q32 locus gives mantle cell lymphoma t(4;14)(p16. 3;q32) Fgfr-1 and mmset: worst prognosis t(14;16)(q32;q23) t(6;14)(p21;q32) Cyclin d3: other translocations involving the igh locus include 8q24 (c-myc), 18q21 (bcl2), 11q23 (mll1) 20q12 (mafb). These are rarer: secondary genetic events become commoner with advanced disease. These include further mutatuons in igh as well as mutations in lamda light chain, del (rb), p18/ras mutations: ras mutations accumulate and correlate with disease stage. Il6, igf1, vegf, sdf1a: bm stroma produces il6.
