SCIENTIFIC PROGRAMME
SESSION I
BIOLOGY OF B-CELL
PRECURSOR ALL
SESSION II
BIOLOGY OF T-CELL ALL
SESSION III
MINIMAL RESIDUAL
DISEASE MONITORING
SESSION IV
INDIVIDUALIZED
MANAGEMENT OF ALL
SESSION V
NEW ADVANCES IN ALL
SESSION VI
CAR T-CELLS &
ALLOGENEIC HSCT
SESSION VII
FRONTLINE
INCORPORATION OF
BITES AND ADCS
SESSION VIII
T-CELL ALL AND
LYMPHOBLASTIC
LYMPHOMA
SESSION IX
PH AND PH-LIKE ALL
SELECTED ABSTRACTS
FOR AN ORAL
PRESENTATION
SELECTED ABSTRACTS
AS E-POSTERS
DISCLOSURES
p.Y931C may reduce ruxolitinib binding affinity by disruption of a critical hydrogen-bond. The
novel JAK2 p.G993A mutation is predicted to alter DFG-loop dynamics by stabilising the JAK2
activation loop. Ba/F3 cells expressing JAK2 fusions harbouring introduced JAK2 p.G993A
mutations were resistant to all tested JAK inhibitors including the type-II inhibitor CHZ-868,
which binds in an allosteric site of JAK2 in addition to the ATP-binding site.
Conclusions
This study demonstrates that the JAK2 ATP-binding site is susceptible to JAK inhibitor resistant
mutations following ruxolitinib exposure in the setting of JAK2r B-ALL, highlighting the
importance of monitoring the emergence of mutations within this region. In addition to
previously described mutations, we identified a novel JAK2 p.G993A mutation that conferred
resistance to both type-I and type-II JAK inhibitors. The JAK2 p.G993A mutation was
postulated to modulate the stability of a conserved domain. Understanding mechanisms of
ruxolitinib resistance, as modelled here, has the potential to inform future drug design and
the development therapeutic strategies for this high-risk cohort.