Transcript Dr Wei`s presentation part 2

Haemapoietic Stem Cell are pluripotent and give rise to all of the haemopoietic cell
under the action of cytokines.
Stem cell are identified by CD34 positivity
and CD117 positivity .
CD117 is the receptor for stem cell factor
MYELOPROLIFERATIVE DISORDERS
Chronic Myeloid Leukemia Ph’ chromosome
Polycythaemia Rubra Vera Jak-2 mutation V617F
95%
Jak-2 exon 12 mutations (6) 3%
Essential Thrombocythaemia Jak-2 mutation 50%
CALR mutation 40%
c-mpl mutation 5%
Primary Myelofibrosis
Jak-2 mutation
50%
MYELODYSPLASTIC DISORDERS
Abnormal looking haemopoitic cells with < 20% blasts in marrow
Refractory cytopaenia with unilineage dysplasia
Refractory cytopaenias with multilineage dysplasias
Refractory anaemia with ringed sideroblasts
Refractory anaemia with excess of blasts.
High Risk MDS
Refractory Anaemia with Excess of Blasts
Secondary MDS from previous chemotherapy
Bad cytogenetics : p53 deletion Chr 17p
Complex cytogenetics >/= 3 abnormalities
MYELODYSPLASTIC/ MYELOPROLIFERATIVE
DISORDERS
Chronic myelomonocytic leukemia
Juvenile myelomoncytic leukemia.
Atypical CML
Myelodysplastic/myeloproliferative disorders unclassified
RARS with marked thrombocytosis
CHRONIC MYELOID LEUKEMIA
Chronic phase
Accelerated Phase
Acute Leukemia within 5 years.
TREATMENT
Alkylating agents
Interferon-alpha
Allogenic bone marrow transplant
Tyrosine Kinase inhibitors since 2003
Imatinib (Glivec)
Dasatinib and nilotinib
SSS
ACUTE LEUKEMIAS
Children
Adults
70% ALL
70% AML
30% AML
20% ALL
10% Mixed Lineage
AML
1970’s
French American British (FAB)
Morphology and Cytochemistry
Myeloperoxidase (MPO) +ve Myeloblasts
Alpha-Napthyl Acetate Esterase +ve for Monoblasts
M1
Immature myeloblasts
M2
Some mature granulocytes
M3
Acute Promyelocytic Leukemia
M4
Acute Myelomonocytic Leukemia
M5
Acute Monocytic Leukemia
M6
Erytholeukemia
M7
Megakaryoblastic Leukemia
M0 in 1988
: MPO –ve but myeloid marker CD13, CD33 positive by flow cytometry
M0
M1
M3
M5
M4
M6
M2
M7
AML RECURRENT CYTOGENETIC
ABNORMALITIES
M2
with t(8;21) RUNX1-RUNX1T1
M4 Eos inv 16 (p13.q22) CBFB-MYH11
M3 t(15;17)
PML-RARA
M4/M5 t(9;11) MLLT3-MLL
AML with dysplasia t(6;9)
AML with thrombocytosis inv(3)(q21;q26.2)
M7 t(1,22)
ACUTE PROMYELOCYTCIC LEUKEMIA
Prone to DIC
Responds to All-trans retinoic Acid ATRA
Responds to low dose Arsenic
ALL RECURRENT CYTOGENETIC
ABNORMALITIES
B ALL
t(9:22)
t(12;21) TEL-AML1 or ETV6-RUNX1
t(1;19)
t(v;11q23) MLL gene rearranged
GENE MUTATION STUDIES
FLT-3
CEBPA
NM1
RUNX
WT1
BAALC
ERG
MN1
(Fms like tyrosine kinase-3)
(CCAAT enhancer-binder protein alpha)
(Nucleophosmin)
TREATMENT
Induction therapies
ALL Vincristine, Dexamethasone, L-asparaginase
AML
Daunorubacin 3 days, Arabinoside-C 7 days
Bone marrow transplant for high risk patients and relapsed
patients
NOVEL AGENTS
Gemtuzamab Anti- CD33
Farnesyl transferase inhibitors
Hypomethylating agents GPC islands to activate tumour suppressor genes.
GENOMICS
Human Genome Project 1990-2003
$3 billion dollars
Multiple institutions China, France, Germany,
Japan, Spain, Uk, USA
25,000 genes.
1.5% of genome are coding genes.
1% regulatory genes
97% non-coding sequences.
NEW GENERATION SEQUENCERS
Whole genome sequencing $1,000 - $5,000
In a little over 24 hrs
TUMOURS STUDIED
Acute leukemias
Bladder
Breast
Hepatocellular carcinoma
Eosophageal
Gastric
Pancreatic
Prostate