Core binding factor acute myeloid leukaemia and c-KIT mutations

Abstract

Abstract. Core binding factor (CBF) acute myeloid leukaemia (AML) represents 5-8% of all AMLs and has a relatively favourable prognosis. However, activating c-KIT mutations are reported to be associated with higher risk of relapse and shorter survival. To verify the incidence and prognostic value of c-KIT mutations in CBF AML, we retrospectively analysed bone marrow samples of 23 consecutive adult patients with de novo CBF AML [14 inv(16) and 9 t(8;21)] treated at a single institution from 2000 to 2011. All patients received standard induction chemotherapy with cytarabine, idarubicin and etoposide; 13 underwent allogeneic stem cell transplantation. c-KIT mutations in exons 8, 9, 10, 11, 13, 14 and 17 were assessed by PCR amplification in combination with direct sequencing. c-KIT mutations (3 in exon 10 and 4 in exon 17) were detected in 7/23 (30.4%) patients, 3 with t(8;21) and 4 with inv(16). No difference in c-KIT mutation status was observed between cases with inv(16) or t(8;21) alone and cases with additional cytogenetic abnormalities. No association between gender, age, white blood cell and platelet count, peripheral blood and bone marrow blast cells at diagnosis, achievement of complete remission, cytogenetic risk groups and Wilms tumour gene 1 (WT1) levels was found. On the contrary, lactate dehydrogenase (LDH) values were higher in mutated than in non-mutated patients (P=0.01). Overall survival (OS) rates were longer in CBF compared to the other types of AML and disease-free survival (DFS) was longer in inv(16) than in t(8;21) AML. OS and DFS were similar in mutated and non-mutated CBF AML patients. Our results confirm a better prognosis for CBF AML than all other AML categories, and for inv(16) than t(8;21) AML. However, no prognostic value for c-KIT mutational status was found in our series. The association between LDH levels and c-KIT mutation would indicate a more active proliferation for mutated CBF AML.

Targeting autophagy potentiates the apoptotic effect of histone deacetylase inhibitors in t(8;21) AML cells

“…The Hsp90 client proteins Akt and c-Kit, involved in autophagy regulation and prosurvival signaling, respectively, might be relevant in t(8;21) AML because ;50% of AML patients show constitutive activation of the phosphatidylinositol 3-kinase/Akt pathway, 40 and activating c-Kit mutations mediating cellular survival are predominantly found in t(8;21) and inv(16) AML subtypes. 41,42 The regulation of autophagy and survival may be tightly linked, as loss of survival signals, which would mimic growth factor starvation, is known to induce autophagy. 43 It will be interesting in future studies to elucidate whether nonhistone targets 5 mM) in the absence or presence of CQ for 16 hours, 800 cells were seeded in Methocult medium in the absence of drugs, and colonies were scored 8 days later.…”

High level of miR-196b at newly diagnosed pediatric acute myeloid leukemia predicts a poor outcome

“…We also found a lowest level of miR-196b in patient with C-Kit mutation compared with others. Earlier studies have found that C-Kit mutation is associated with unfavorable prognosis of adult AML with t (8; 21) ( Boissel et al, 2006[2]), and AML children with t (8;21) or CBF-rearrangement (Shimada et al, 2006[28]; Manara et al, 2014[17]), yet other investigations indicated that no significant relevance existed between C-Kit mutation and the prognosis of AML children and adults (Pollard et al, 2010[23]; Goemans et al, 2005[9]; Shih et al, 2008[27]; Riera et al, 2013[26]). As is mentioned before, we forcefully demonstrated the prognostic relevance of low miR-196b expression to favorable outcome.…”

Genetic Mutations in Acute Myeloid Leukemia

“…Эта мутация не-однократно описана у больных ОМЛ с характерными изменениями хромосом, а именно с t(8;21)(q22;q22) и inv(16)/t(16;16)(q13;q22) [106,107]. Эти изменения хро-мосом объединяются в одну группу, т. к. при них повреж-даются гены, кодирующие субъединицы фактора CBF, и характеризуются благоприятным прогнозом заболевания.…”

“…Прогноз заболевания в данном случае зависит от типа мутации, а также от варианта хромосомной патологии и возраста пациента [106,110]. В противоположность такому мнению есть единичные сообщения о независи-мости прогноза CBF-ассоциированного ОМЛ от наличия мутации KIT [107]. Кроме того, во многих исследованиях показано, что присутствие мутации KIT свидетельствует о плохом прогнозе заболевания у больных с t(8;21), но не с inv(16)/t(16;16) [108,[111][112][113].…”