BCR::ABL1 T315I

aka T315I, BCR-ABL T315I, ABL1 T315I, T315I mutation, gatekeeper mutation CML

T315I is the gatekeeper mutation in the ABL1 kinase that defeats imatinib, dasatinib, nilotinib and bosutinib. Ponatinib and asciminib are the two drugs approved for it.

The threonine-to-isoleucine change at the gatekeeper residue removes a hydrogen bond the first- and second-generation inhibitors need and adds steric bulk. It is detected by Sanger or next-generation sequencing of the kinase domain when BCR::ABL1 levels rise. Ponatinib (Iclusig) is labelled for T315I-positive CML in any phase and T315I-positive Ph+ ALL; asciminib (Scemblix), which binds the myristoyl pocket rather than the ATP site, is labelled for Ph+ CML in chronic phase with the T315I mutation at a higher dose. Allosteric plus ATP-site combinations are in trials for compound mutations.

Part ofBCR::ABL1 (Philadelphia chromosome)· BCR-ABL1Other readoutsBCR::ABL1 transcript All readouts

BCR::ABL1 (Philadelphia chromosome): what it is and how drugs act on it · animated schematic, not to scale

Target · the protein and the cell it sits on
Drug · antibody, small molecule, cell or radioligand
Effect · signal, damage or kill

In plain words · The fusion that defines chronic myeloid leukaemia and a quarter of adult acute lymphoblastic leukaemia; the first cancer driver ever switched off by a pill.

Sequencing 2 approval thresholds

What it means for a patient

If your leukaemia's BCR::ABL1 level has risen and sequencing finds T315I, the usual tablets will no longer work; ponatinib or asciminib are the two approved options and a transplant may be discussed. Testing for the mutation is done from a blood sample whenever response is lost.

Written only from the label or guideline text cited on this page. Not medical advice; your own report and the reading your team gives it come first.

Scoring rule

The ABL1 c.944C>T (p.T315I) substitution in the BCR::ABL1 kinase domain by Sanger or next-generation sequencing of blood or marrow RNA.

“Ph+ CML in CP with the T315I mutation.”
SCEMBLIX prescribing information

Thresholds used in approvals

Threshold	Drug	Cancer	Regulator	Source
T315I-positive The Iclusig label also covers chronic, accelerated and blast phase CML with the T315I mutation.	Ponatinib	Chronic myeloid leukaemia (CML)	FDA	label
T315I mutation, chronic phase	Asciminib	Chronic myeloid leukaemia, chronic phase	FDA	label

Drugs whose label names it

Ponatinib Asciminib

Tests that measure it

FoundationOne Heme

Trials that name this readout

Matched on the name and aliases of the readout in the title, setting and summary of each trial; a match is a mention, not proof the readout was an entry criterion.