Clonal Heterogeneity Reflected by PI3K-AKT-mTOR Signaling in Human Acute Myeloid Leukemia Cells and Its Association with Adverse Prognosis

Abstract

Clonal heterogeneity detected by karyotyping is a biomarker associated with adverse prognosis in acute myeloid leukemia (AML). Constitutive activation of the phosphatidylinositol-3-kinase-Akt-mechanistic target of rapamycin (PI3K-Akt-mTOR) pathway is present in AML cells, and this pathway integrates signaling from several upstream receptors/mediators. We suggest that this pathway reflects biologically important clonal heterogeneity. We investigated constitutive PI3K-Akt-mTOR pathway activation in primary human AML cells derived from 114 patients, together with 18 pathway mediators. The cohort included patients with normal karyotype or single karyotype abnormalities and with an expected heterogeneity of molecular genetic abnormalities. Clonal heterogeneity reflected as pathway mediator heterogeneity was detected for 49 patients. Global gene expression profiles of AML cell populations with and without clonal heterogeneity differed with regard to expression of ectopic olfactory receptors (a subset of G-protein coupled receptors) and proteins involved in G-protein coupled receptor signaling. Finally, the presence of clonal heterogeneity was associated with adverse prognosis for patients receiving intensive antileukemic treatment. The clonal heterogeneity as reflected in the activation status of selected mediators in the PI3K-Akt-mTOR pathway was associated with a different gene expression profile and had an independent prognostic impact. Biological heterogeneity reflected in the intracellular signaling status should be further investigated as a prognostic biomarker in human AML.

The PI3K-Akt-mTOR Signaling Pathway in Human Acute Myeloid Leukemia (AML) Cells

“…This is probably again reflected in the heterogeneity between leukemic cells with regard to energy metabolism, amino acid metabolism and arachidonic acid metabolism, supported by the finding that modulation of arachidonic acid metabolism alters the activation of mTOR and its downstream mediators [80]. The activation status of the PI3K-Akt-mTOR pathway is probably also reflected in clonal heterogeneity and different gene expression profiles [79]. The PI3K-Akt-mTOR pathway is important for disease development and chemosensitivity, and activation of this pathway has prognostic impact in AML [79,95].…”

“…Dysregulation of the PI3K-Akt-mTOR signaling pathway subsequent to oncogene activating mutations, oncogene amplification, upstream activation of RTKs, or inactivation of tumor suppressor genes has been demonstrated in many human malignancies, including AML [79,80]. The PI3K-Akt-mTOR pathway is central for hematopoietic cells, and regulates crucial functions such as proliferation, differentiation, and survival.…”

“…The PI3K-Akt-mTOR pathway is central for hematopoietic cells, and regulates crucial functions such as proliferation, differentiation, and survival. This pathway seems to be constitutively activated in 60% of AML patients, and this activation seems to be associated with decreased overall survival [79][80][81][82][83]. Mutations in membrane bound-proteins, such as RTKs or GTPases, are major causes of dysregulated PI3K-Akt-mTOR signaling and are observed in 55% of AML cases [13,66].…”

“…AML patients harbor leukemia cells that display heterogeneous constitutive PI3K-Akt-mTOR activation profiles [79,95]. These dissimilarities are part of more complex phenotypic variations, including transcriptional regulation, cross signaling, and cell communication and may be influenced by growth factor stimulation or various inhibitors of pathway activation [70,79,80].…”

“…AML patients harbor leukemia cells that display heterogeneous constitutive PI3K-Akt-mTOR activation profiles [79,95]. These dissimilarities are part of more complex phenotypic variations, including transcriptional regulation, cross signaling, and cell communication and may be influenced by growth factor stimulation or various inhibitors of pathway activation [70,79,80]. This is probably again reflected in the heterogeneity between leukemic cells with regard to energy metabolism, amino acid metabolism and arachidonic acid metabolism, supported by the finding that modulation of arachidonic acid metabolism alters the activation of mTOR and its downstream mediators [80].…”