IT IS SIGNALLING PATHWAY FOR PATHOGENESIS FOR ACUTE MYELOID LEUKEMIA

1. Acute Myeloid Leukemia
Pathway Signalling
Prepared And Presented By:
Ankan Sarkar
Pharmacology And Toxicology
NIPERA1820PC02

2. ACUTE MYELOID LEUKEMIA
 Acute myeloid leukemia (AML) is characterized by an increase in the
number of myeloid cells in the Bone Marrow and an arrest in their
maturation, frequently resulting in hematopoietic insufficiency.
 Dysregulated differentiation, uncontrolled growth and inhibition
of apoptosis lead to accumulation of immature myeloid
progenitor cells and progression of oncogenic expression.
 The management of acute myeloid leukaemia (AML) in India remains a
challenge. In a two-year prospective study there were 380 newly
diagnosed AML patients In CMC Vellore Data. The median age of newly
diagnosed patients was 40 years (range: 1–79; 12.3% were ≤ 15 years,
16.3% were ≥ 60 years old) and there were 244 (64.2%) males.
WHO data 2018

3. Difference Between Normal And AML Haematopoiesis
The molecular pathogenesis of acute myeloid leukemia;
Bjorn Steffen, Carsten Muller-Tidow, Wolfgang E. Berdel,Hubert Serve at.al, Elsevier

4. OVERVIEW
SYMPTOMS
Pancytopenia,anemia,hepatosplenomegaly, Pallor,
petechiae, ecchymosis, Bone tenderness
WHO CLASSIFICATION
i. AML with certain genetic abnormalities
ii. AML with multilineage dysplasia (more
than one abnormal myeloid cell type is
involved)
iii. AML related to previous chemotherapy or
radiation
iv. AML not otherwise specified
– undifferentiated AML (M0)
– AML with minimal maturation (M1)
– AML with maturation (M2)
Gingival Infiltration in
Monocytic Variant of AML

5. OVERVIEW ABOUT APOPTOSIS IN CELL SURVIVAL
AND CANCER PROGRESSION
 Apoptosis: It is programmed cell death, is a normal component of the
development and health of multicellular organisms.
 Cells die in response to variety of stimuli and in Controlled Regulated
Fashion.
 Cancer is often characterised by TOO LITTLE APOPTOSIS or TOO
MANY MUTATIONS avoid normal cellular signals.
MUTATIONS
Pathogenesis of leukemia explained by two classes of alterations of
oncogenes as a result of chromosomal aberrations
i. CLASS I mutations (confers proliferative/survival stage of cells)
Current Status: More Than 10 Different PTK
i. CLASS II mutations(Impairs differentiation of haematopoietic cells)

6. APOPTOTIC SIGNALLING FROM DEATH
RECEPTOR
• Death inducing ligand binds to DR and cause
generation of ceramide
• Ceramide release is to promote LIPID RAFT
FUSION for membrane protein trafficking
• Death receptors get clustered, amplifying
apoptotic signals
In cancer these all cascade stops and resulting increase in proliferation and
deregulation of apoptosis. Apoptosis; Phil Dash, Basic Medical Sciences, St.George’s, University of London

7. JAK JAK
P
P
STAT1
STAT2
PP
P
PIM1 AND
PIM2
Tyrosine kinase
associated
receptor
cytokines
GENE EXPRESSION
ANTIAPOPTOSIS
JAK STAT PATHWAY INDUCING AML
Dimerisation
NUCLEUS
AML

8. PP
GDP
RAS RAS
GTP
RAF
MEK
ERK/MAPK
cJUN cFOS
BIM
APOPTOSIS
AML
AML
GRB2
SOS
SH2
Growth factor’s
Growth factor
receptor’s
Cytosol
RAS/RAF/MEK/ERK pathway In AML
Chembiodraw ultra 14.0

9. P P PI3K PIP2 PIP3
PKC
PDK
1
NF-kB AKT
mTORC1
Bad
mTORC2
MAPK Pathway
APOPTOSIS
CELL PROLIFERATION
AML
CELL PROLIFERATION
CELL SURVIVAL
AML
GPCR
Receptor
tyrosine kinase
Growth
factor’s
PI3K, AKT and
mTOR Pathway In
AML
TRANSCRIPTION

10. DEREGULATION IN AML
Disruptions in the highly regulated apoptotic pathway can lead to tumor
development due to deregulation of cell death. (Apoptosis)
Ras
RAF
MEK
ERK
PI3K
AKT
SURVIVAL OF CELLS
CELL PROLIFERATION
*FLT3 Inhibitor-
Midostaurin,
Lestaurtinib
**Ckit Inhbitor-
Imatinib
DeregulationofsignallingpathwaysinAcute
myeloidleukemia;ClaudiaScholl,GaryGillilandat.
al

11. Signal transduction
pathways in AML
Role of signalling pathways in acute
myeloid leukemia; Maha Abdullah
and Zainina Senam at.al

12. TARGETTING NOVEL SIGNALLING PATHWAYS IN
RESISTANT AML
A. CREB(cyclic AMP response element binding protein)
TARGETS:
i. Downregulation of CREB by Mir34b
B. Targeting AML with BH3 mimetics
Aberrant overexpression of BcL2 family
Targets:
Using BH3 mimetics by BcL2/BcLxL antagonist
Targeting novel signaling pathways for resistant acute myeloid leukemia
Kathleen M. Sakamoto , Steven Grant et.al

13. Abbreviations
AML-Acute myeloid leukemia
JAK-Janus kinases
STAT-Signal transducer & activator of transcription
Pim1-Proto-oncogene serine/threonine-protein kinase 1
GRB2-Growth factor receptor-bound protein 2
SOS- Son of Sevenless
RAF-Rapidly Accelerated Fibrosarcoma
MEK-Mitogen-activated protein kinase kinase
ERK/MAPK- mitogen-activated protein kinases
BIM- Bcl-2-like protein 11
PI3K-phosphoinositide 3-kinase
PIP2/PIP3-Phosphatidylinositol Biphosphate/Phosphatidylinositol trisphosphate
AKT/PKB-Protein kinase B
NF-Kb-nuclear factor kappa-light-chain-enhancer of activated B cells
mTORC1/mTORC2-mammalian target of rapamycin complex 1/2
PKC- Protein kinase C
FLT3- fms related tyrosine kinase 3
BcL-2/BcL-XL- B cell lymphoma 2/B cell lymphoma Extra Large

14. REFERENCES
1.Chembiodraw ultra 14.0
2.Role of signalling pathways in acute myeloid leukemia; Maha Abdullah and
Zainina Senam at.al
3. Deregulation of signalling pathways in Acute myeloid leukemia; Claudia Scholl,
Gary Gilliland at. al
4. Targeting novel signaling pathways for resistant acute myeloid leukemia
Kathleen M. Sakamoto , Steven Grant , Diana Saleiro, John D. Crispino, Nobuko
Hijiya, Francis Giles at.al
5.Apoptosis; Phil Dash, Basic Medical Sciences, St.George’s, University of London
6. The molecular pathogenesis of acute myeloid leukemia;
Bjorn Steffen, Carsten Muller-Tidow, Joachim Schwable, Wolfgang E. Berdel,Hubert
Serve at.al, Elsevier
7. Acute myeloid leukemia – strategies and challenges for targeting oncogenic
Hedgehog/GLI signaling; Fritz Aberger, Evelyn Hutterer,Christina Sternberg at.al
8. Miscellaneous