Abstract 2402

Poster Board II-379

The MYB proto-oncogene encodes a nuclear transcription factor with an essential role in proliferation, lineage commitment, and differentiation of hematopoietic progenitor cells. Proper levels of MYB are known to be important during hematopoietic cell development, and the Myb gene is a frequent target of retroviral insertions in myeloid, B- and T-cell leukemias in the mouse. Overexpression of MYB in T-acute lymphoblastic leukemia (T-ALL) causes a differentiation block of the T cells, and it has been shown that NOTCH1 mutation and MYB duplication cooperate in the pathogenesis of T-ALL. Our aim was to study the role of MYB in the pathogenesis of acute myeloid leukemia (AML), and to investigate its potential as a target for therapy. We functionally characterized MYB in 15 AML cell lines. Twelve of the 15 cell lines tested had MYB overexpression. Knockdown of MYB by siRNA in these cell lines caused decreased cell viability and proliferation, and reduced the clonogenic capacity, that could be explained in some cell lines by changes on the stage of cell differentiation. These results show that MYB overexpression is involved in the pathogenesis of AML. Moreover, knockdown of MYB in combination with common AML treatments (Idarubicin, Cytarabine and Sorafenib) had a strong synergistic effect on proliferation and viability of cells, suggesting that MYB could be a new target for therapy in AML. These observations prompted us to quantify MYB expression in a cohort of 159 patients with AML at diagnosis. We detected MYB overexpression in 14.5% (23/159) patients, with a higher prevalence within the intermediate prognosis group (17/83, 20.5%), particularly in patients with normal karyotype (NK) (14/62, 22.6%). Interestingly, 33% of patients without FLT-3 ITD and NPM1 mutations had MYB overexpression. To study the prognosis impact of MYB overexpression in AML, we performed a survival analysis in a preliminary series of 100 AML patients at diagnosis. As expected, significant differences in OS according to age, complete remission and cytogenetic prognostic group were found (p<0.01). MYB overexpression had no significant impact in the OS; however, this genetic marker allowed distinguishing a group of patients with a worse outcome within the group that did not get complete remission after treatment. Recently it has been described that MYB duplication causes elevated MYB expression in T-ALL; we detected duplication of MYB in 2 of 13 AML cell lines and in 2 patients with MYB overexpression (2/23, 8.6%). In conclusion, these results show that aberrant expression of MYB is involved in the activation of pathways responsible for the increased proliferative and clonogenic capacity that is characteristic of AML, independently of other genetic aberrations. Moreover, we show that MYB overexpression is a recurrent event in AML, especially in the subgroup of patients with NK, and that MYB could cooperate with other mutations in the leukemic transformation, as described previously in T-ALL. The synergistic effect of combined treatments with MYB knockdown, suggest that MYB silencing could be a new target for therapy in patients with AML and MYB overexpression.


No relevant conflicts of interest to declare.

Author notes


Asterisk with author names denotes non-ASH members.