Monocytic Differentiation in Acute Myeloid Leukemia Cells: Diagnostic Criteria, Biological Heterogeneity, Mitochondrial Metabolism, Resistance to and Induction by Targeted Therapies
Metadatos
Mostrar el registro completo del ítemEditorial
MDPI
Materia
Acute myeloid leukemia Prognosis Differentiation
Fecha
2024-06-08Referencia bibliográfica
Bruserud, Ø. et. al. Int. J. Mol. Sci. 2024, 25, 6456. [https://doi.org/10.3390/ ijms25126356]
Resumen
We review the importance of monocytic differentiation and differentiation induction in
non-APL (acute promyelocytic leukemia) variants of acute myeloid leukemia (AML), a malignancy
characterized by proliferation of immature myeloid cells. Even though the cellular differentiation
block is a fundamental characteristic, the AML cells can show limited signs of differentiation. According
to the French–American–British (FAB-M4/M5 subset) and theWorld Health Organization
(WHO) 2016 classifications, monocytic differentiation is characterized by morphological signs and the
expression of specific molecular markers involved in cellular communication and adhesion. Furthermore,
monocytic FAB-M4/M5 patients are heterogeneous with regards to cytogenetic and molecular
genetic abnormalities, and monocytic differentiation does not have any major prognostic impact for
these patients when receiving conventional intensive cytotoxic therapy. In contrast, FAB-M4/M5
patients have decreased susceptibility to the Bcl-2 inhibitor venetoclax, and this seems to be due to
common molecular characteristics involving mitochondrial regulation of the cellular metabolism
and survival, including decreased dependency on Bcl-2 compared to other AML patients. Thus, the
susceptibility to Bcl-2 inhibition does not only depend on general resistance/susceptibility mechanisms
known from conventional AML therapy but also specific mechanisms involving the molecular
target itself or the molecular context of the target. AML cell differentiation status is also associated
with susceptibility to other targeted therapies (e.g., CDK2/4/6 and bromodomain inhibition), and
differentiation induction seems to be a part of the antileukemic effect for several targeted anti-AML
therapies. Differentiation-associated molecular mechanisms may thus become important in the future
implementation of targeted therapies in human AML.