Title:New Developments of Differentiation Therapy of Acute Myeloid Leukemia
Volume: 14
Issue: 2
Author(s): Germana Castelli, Elvira Pelosi and Ugo Testa*
Affiliation:
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome,Italy
Keywords:
Cell differentiation, clinical trials, differentiation inducers, leukemia, molecular genetics, targeted therapy,
therapy.
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.
