Acute lymphoblastic leukaemia and MLL translocations Flashcards
ALL
Acute lymphoblastic leukaemia
Malignant (clonal) disease of the bone marrow in which early lymphoid precursors proliferate and replace the normal haematopoietic cells of the marrow
ALL epidemiology
Most common childhood cancer
80% of acute leukaemia cases
20% of cases in adults
Peak at age 2-5; age 50
Presentation of ALL
Pancytopenia; Fatigue; easy bruising; bleeding; extremity pains due to build up of lymphoblasts in bone marrow
Clinical presentations (physical exam) ALL
Pallor
Ecchymoses
Petechiae
LAD
Hepatosplenomegaly
Clinical presentations (lab abnormalities) ALL
Anaemia
WBC vary
- 0.1 (20-40%)
- 100k (10-16%)
Usually decreased platelets (pancytopenia)
Increased LD, Uric acid
Chest x-ray; enlarged mediastinum
Lumbar puncture; CSF to investigate CNS involvement (5-10
Morphologic diagnosis of ALL
FAB classification
L1 small uniform blasts (Paedicatric ALL)
L2 larger, more variable sized blasts (adult ALL)
L3 uniform cells with basophilic and sometimes vacuolated cytoplasm (mature B cell ALL)
Immunophenotyping of B-lineage ALL markers
CD19, CD20, CD22, CD24 and CD79a
75% of ALL cases
Immunophenotyping of T-lineage ALL markers
CD1a, CD2, CD3(membrane cytoplasm), CD4, CD5, CD7 and CD8, CD2, CD5 and CD7
Treatment of ALL
Systemic chemotherapy
Prophylactic CNS chemotherapy and sometimes CNS radiation
For Phil. + ALL, tyrosine kinase inhibitor
Immunotherapy, targeted therapy, stem cell transplantation, radiation
Palliative care
____________ is the favourable number in ALL
Hyperdiploid
____________ non-favourable number in ALL
Hypodiploid
Favourable translocation in ALL
T(12;21) - tel-AML -1 fusion 20% of ALL cases
Unfavourable translocations in ALL
T(1;19) E2A-PBX1
T(9;22) Philadelphia BCR::ABL
MLL (11q23)
MLL
Mixed lineage leukaemia
Chromosome 11 q23
Found in various immunophenotypes in AML and ALL
Normally expressed in bone marrow haematopoietic cells
MLL is cleaved by ______ to generate what two subunits?
Taspase 1
MLLN and MLLC
RNA polymerase II binds promoter but cannot proceed with transcription without _______________________ on the histone core
Specific methylation marks
MLL mediates methylation of _______within the promoter region of the genes
H3K4
Histone H3 and lysine 4 methylation marks permit transcription initiation and __________ allows for extension
H3K36
Major MLL fusion partner genes are:
AF4 - ALL
AF9 - AML
ENC - ACC. And AMC
MLL partial tandem duplication
Most commonly results from duplication of exons 5-12 and inserted before exon 11 or 12
Creates a unique in-frame fusion of exon 11/12 upstream of exon 5
Most often found in adult de novo AML with normal cytogenetics trisomy 11
De novo clinical pathology of MLL leukaemia
MLL arrangements are found in approximately:
5% of ALL
5-10% of AML
Basically all cases of MLL
Therapy related clinical pathology of MLL leukaemia
Therapy related
5-10% of 11q23 cases are found mainly following a treatment anti-topoisomerase II, or an intercalating topoisomerase II inhibitor
Also after alkylating agent treatment and/or radiotherapy - the prior cancer is variable
HOX gene expression ___________ as haematopoietic cells differentiate
Decreases
HOX genes and MLL
Expression must be terminated too early for normal differentiation to complete
Upregulation of HOX genes is central to MLL fusion leukaemia (precursors are unable to differentiate)
Minimal residue disease and targets
Residual tumour cells undetected by conventional procedures
Patients in clinical emission may still harbour 10^10 malignant cells
Chromosomal translocations are ideal targets for MRD monitoring
- detection is relatively simple involving PCR with a single set of primers
- chromosomal aberrations are pathogenically related to the neoplastic process and they represent a stable molecular marker
ALL in identical twins
1st hit => mutation in uteri ETV6/RUNX1
2nd hit => secondary mutation ETV6 deletion or gain of RUNX1 => ALL
Mutation occurred in one twin, cellular transmission through the placenta
MLL partial tandem duplication
BAD PROGNOSIS
Found in adult de novo AML w/ normal cytogenetics or trisomy II
What mediates the binding of MLLN to DNA sequences?
AT-hook motifs mediated binding to AT-rich genomic DNA sequences
The transcriptional activation domain recruits what co-activator for transcription in MLL epigenetic regulation
CREB-binding protein
Within the N terminal region of the MLL protein the transcriptional repression domain contains what two functional subunits?
RD1 contains DNA methyltrasnferase homology domain
RD2 recruits histone deacetylases HDAC1 and HDAC2
What does the C terminal domain of the MLL protein contain?
Histone H3 lysine 4 methyltrasnferase activity
Why is MLL a master epigenetic regulator?
RNA polymerase 1 binds promoter but cannot proceed without specific methylation marks on histone core
Histone H3 Lysine 4 methylation marks promote transcription
MLL mediates methylation of H3K4
What does an MLL fusion protein consist of?
N-terminus of MLL and C terminus of a fusion partner gene
