Download CML Biology Session Saturday – Prognosticability

Saturday June 11th session PM – CML Biology
Enhanced expression of the Hedgehog pathway target gene PTCH1 predicts inferior response
to Imatinib in CML
On the premises that TKI’s for CML have provided great success, BCR ABL1 positive LSC persist
even after long-term or life-long TKI therapy. The survival of the LSC could potentially lead to relapse
and/or progression. Recent findings have indicated that activity in the Hh signaling pathway is crucial for
their survival (LSC). Interestingly the level of Hh activity can be quantified by the expression of its
downstream target genes GLI1 and PTCH1. This study wants to compare the range of expression of
PTCH1 in CML patients at diagnosis and compare it to the range of expression, and thus the level of Hh
activity to the clinical outcomes of the patients studied. Interestingly they used RQ-PCR with the GUSB
housekeeping gene to look at the cDNA samples from peripheral blood of 85 CML unselected patients at
the time of diagnosis. IM was given to these patients as front line therapy (they were all in CP). A second
cohort of 31 patients was identified for validation of clinical associations. The Kaplan-Meier method was
used ot calculate the probabilities of OS,PFS and EFS. A receiver-operating characteristic (ROC) curve
method waas used to calculate a threshold for poor response. The median level of PTCH1 expression
relative to GUSB was 3X10-4 (range 0 to 3.7X10-1). It is important to note that the 59 patients with a low
expression of PTCH1 at dx (calculated to be at or below the 59th percentile of the expression range) had a
superior seven year probability of CCyR, MMR, EFS and OS than the 26 patients with a high expression.
Very importantly the expression of PTCH1 was an independent predictor for OS, PFS and CCyR, but very
importantly, its predictor value was independent of the Sokal score. Of interest is that the CD34 count in
the bone trephine and the percentage of blast in the pheripheral blood at diagnosis was also comparable
between patients with low (3.9%-2.8%) and high (4.9% and 2.7%) PTCH1 expression (p=0.72 and p=0.88
respectively). Furthermore the predictive value of PTCH1 was validated in the cohor of 31 patients. This
study showed that PTCH1 has a very high potential to predict responses to IM in CML. What the interpatient variability of Hh activity shows us is that there may be similar variability of this pathway in the
HSCs. This hypothesis is supported by the observation tahta BCR ABL1 increases Hh signaling in
progentiro and stem cells to a comparable degree relative to normal counterparts. So, the authors are
stating that variability in the Hh pathway may representa a plausible mechanism by which the CML clone
in some patients escapes the inhibitory effects of IM and becomes a source of complete relapse.
Note: I have copied the data from the abstract to ensure that it was not misinterpreted.
The references for this abstract are:
Abstract 0522
ENHANCED EXPRESSION OF THE HEDGEHOG PATHWAY TARGET GENE PTCH1 PREDICTS
INFERIOR RESPONSE TO IMATINIB IN CHRONIC MYELOID LEUKEMIA
Author
Daghistani, Mustafa, Imperial College London, London, United Kingdom
Co-author(s)
Khorashad, JS, Imperial College London, London, United Kingdom
Milojkovic, D, Imperial College London, London, United Kingdom
Ibrahim, AR, Imperial College London, London, United Kingdom
May, PC, Imperial College London, London, United Kingdom
Gerrard, G, Imperial College London, London, United Kingdom
Goldman, JM, Imperial College London, London, United Kingdom
Apperley, JF, Imperial College London, London, United Kingdom
Foroni, L, Imperial College London, London, United Kingdom
Marin, D, Imperial College London, London, United Kingdom
Reid, AG, Imperial College London, London, United Kingdom (Presenting author)