Mutations

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I found this information in the U.K. Lancet about mutations. Thought some of

you might be interested or have had past problems with mutations. I know some

who have.

Most mutations have been detected in patients with acute leukaemia but some

were also detected in patients with chronic-phase CML who became resistant to

imatinib, most without achieving a complete cytogenetic response.38 These

mutations were not observed in samples obtained before imatinib treatment. Since

mutations can be identified only when mutated cells account for at least 10% of

the overall cell population, these data indicate that mutant cells were present

at low prevalence before imatinib therapy. This idea is not surprising given

that these mutations do not confer any growth advantage in the absence of

imatinib. The short time required for the emergence of resistance suggests that

mutants were present before treatment and were selected only because of the

specific pressure exerted by imatinib. The study by Roche-Lestienne and

colleagues, who used a sensitive technique called allele specific

oligonucleotide-PCR to detect mutations, supports such a conclusion.45 These

data also indicate the extreme degree of heterogeneity of Ph-positive acute

leukaemias; clones harbouring mutations probably exist in almost all genes and

so could be selected if a specific pressure were applied.

Mutations have not been found in patients who did not initially respond to

imatinib (primary resistance, table 1). Thus, there are mechanisms other than

mutations that can lead to the development of resistance. In these patients,

imatinib was unable to exert a selective pressure because it could not eliminate

cells.

BCR-ABL mutations also seem to be significantly more frequent in patients

with lymphoid leukaemia (ALL, lymphoid blast-crisis CML) than in patients with

myeloid leukaemia (table 1; 26 of 30 [87%] versus 27 of 47 [57%], p=0·01).

The two identified mechanisms of resistance to imatinib (BCR-ABL mutations

and amplification) probably account for almost all cases of resistance in

patients with lymphoid leukaemia, whereas additional mechanisms such as

mutations outside the ABL catalytic domain or changes in imatinib

cellular-transport mechanisms34 could be present in some patients with myeloid

leukaemias and in patients who do not initially respond to imatinib.

http://www.thelancet.com/journals/lanonc/article/PIIS1470204503009793/fulltext#a\

rticle-outline