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New Developments of Differentiation Therapy of Acute Myeloid Leukemia

[ Vol. 14 , Issue. 2 ]

Author(s):

Germana Castelli, Elvira Pelosi and Ugo Testa   Pages 86 - 105 ( 20 )

Abstract:


Background: A typical feature of acute myeloid leukemia (AML) consists in the blockade of the cell differentiation process. Many experimental studies have shown that some chemical compounds induce the selective differentiation of hematopoietic cell lines, thus supporting the rationale of using these agents to treat AML by forcing these cells to undergo a process of terminal differentiation. From these studies emerged the potential of all-trans retinoic acid (ATRA) to induce the differentiation of acute promyelocytic cells (APLs) and to treat these patients. The introduction of ATRA in the therapy of these patients improved the treatment of APLs, providing evidence that ATRA, combined with standard chemotherapy or arsenic trioxide (ATO) gives a curative effect in most of these patients. Attempts to emulate the effects of ATRA using other differentiation agents have failed.

Results: The recent identification of new AML subsets classified according to specific molecular abnormalities and the development of agents selectively targeting these leukemia biomarkers led to a renewed interest for the differentiation therapy. It was shown that inhibition of mutant FLT3 or of mutant IDH1/2 exerts a significant anti-leukemia effect in part mediated by induction of cell differentiation. Preclinical studies strongly support the use of these inhibitors in combination with ATRA. On the other hand, recent observations indicate that various modulators of the epigenetic response (such as DNMT3A or LSD1 inhibitors) restore the sensitivity of non-APL AML blasts to the differentiative effect of ATRA.

Conclusion: These observations suggest new successful developments of AML differentiation therapy in the near future.

Keywords:

Cell differentiation, clinical trials, differentiation inducers, leukemia, molecular genetics, targeted therapy, therapy.

Affiliation:

Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome

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