CHRONIC MEYLOID LEUKAEMIA

Question 1

Why CML represents an exception to tumor heterogeneity?

Answer 1

Philadelphia chromosome: translocation between 9 and 22, formation of BCR-Abl tyrosine kinase in pluripotent hematopoietic stem cells
Maintenance of differentiation capacity: good prognostic marker
Chronic tumor: slow progression and affects old individuals (between 50 and 60 y.o.)
Natural progression: chronic > accelerated > blast crisis

Question 2

CML therapy

Answer 2

In the past: high doses of chemotherapy or IFN-alpha
In many cases: allogeneic HSCT
TKIs
Response to therapy: hematological response, cytogenetic response and molecular response
First TKI: Imatinib (Gleevec), 90% of patients respond with at least hematological response, mechanism of action
Wide spectrum TKIs: Nilotinib and Dasatinib
Effects of TKI therapy and challenges
Mechanisms of resistance

Question 3

Alternative pathways activated by leukemic stem cells

Answer 3

Shh signaling pathway: Smoothened inhibitors
Wnt/Beta-catenin signaling pathway: explain the pathway, PP2A activators
FOXO-3A pro-apoptotic function: explain the function and how it changes in leukemic stem cells
PML protein: up regulation in CD34+ leukemic cells for their maintenance in the quiescence state
Ras: farnesyl-transferase inhibitors
Jak-STAT pathway: growth factors receptor involvement, inhibitors
Epigenetic modifications: histone deacetylase inhibitors to block the formation of heterochromatin
Proteasome inhibition
Autophagy inhibition

Question 4

PCR in tumors

Answer 4

PCR: programmed cell removal
Steps of PCR
Mechanisms to resist to PCR > checkpoint inhibitors immunotherapy