Am J Blood Res 2013;3(1):29-51
Review Article
Gene mutations and molecularly targeted therapies in acute myeloid leukemia
Eleftheria Hatzimichael, Georgios Georgiou, Leonidas Benetatos, Evangelos Briasoulis
Department of Hematology, University of Ioannina, Ioannina, Greece; Unilabs, Département d’Hématologie, Genève,
Switzerland; Blood Bank, General Hospital of Preveza, Preveza, Greece
Received December 17, 2012; Accepted January 7, 2013; Epub January 17, 2013; Published January 25, 2013
Abstract: Acute myelogenous leukemia (AML) can progress quickly and without treatment can become fatal in a short period
of time. However, over the last 30 years fine-tuning of therapeutics have increased the rates of remission and cure.
Cytogenetics and mutational gene profiling, combined with the option of allogeneic hematopoietic stem cell transplantation
offered in selected patients have further optimized AML treatment on a risk stratification basis in younger adults. However
there is still an unmet medical need for effective therapies in AML since disease relapses in almost half of adult patients
becoming refractory to salvage therapy. Improvements in the understanding of molecular biology of cancer and identification of
recurrent mutations in AML provide opportunities to develop targeted therapies and improve the clinical outcome. In the
spectrum of identified gene mutations, primarily targetable lesions are gain of function mutations of tyrosine kinases FLT3,
JAK2 and cKIT for which specific, dual and multi-targeted small molecule inhibitors have been developed. A number of
targeted compounds such as sorafenib, quizartinib, lestaurtinib, midostaurin, pacritinib, PLX3397 and CCT137690 are in
clinical development. For loss-of-function gene mutations, which are mostly biomarkers of favorable prognosis, combined
therapeutic approaches can maximize the therapeutic efficacy of conventional therapy. Apart from mutated gene products,
proteins aberrantly overexpressed in AML appear to be clinically significant therapeutic targets. Such a molecule for which
targeted inhibitors are currently in clinical development is PLK1. We review characteristic gene mutations, discuss their
biological functions and clinical significance and present small molecule compounds in clinical development, which are
expected to have a role in treating AML subtypes with characteristic molecular alterations. (AJBR1212005).
Keywords: Acute myeloid leukemia, targeted therapy, mutation, FLT3, NPM1, CEBPA, JAK2
Address all correspondence to:
Dr. Eleftheria Hatzimichael
Academic Department of Haematology
University Hospital of Ioannina
St. Niarchou Av, 45110 Ioannina, Greece.
Tel/Fax: +302651099615
E-mail: ehatzim@cc.uoi.gr; eleftheria.chatzimichail@jefferson.edu
Review Article
Gene mutations and molecularly targeted therapies in acute myeloid leukemia
Eleftheria Hatzimichael, Georgios Georgiou, Leonidas Benetatos, Evangelos Briasoulis
Department of Hematology, University of Ioannina, Ioannina, Greece; Unilabs, Département d’Hématologie, Genève,
Switzerland; Blood Bank, General Hospital of Preveza, Preveza, Greece
Received December 17, 2012; Accepted January 7, 2013; Epub January 17, 2013; Published January 25, 2013
Abstract: Acute myelogenous leukemia (AML) can progress quickly and without treatment can become fatal in a short period
of time. However, over the last 30 years fine-tuning of therapeutics have increased the rates of remission and cure.
Cytogenetics and mutational gene profiling, combined with the option of allogeneic hematopoietic stem cell transplantation
offered in selected patients have further optimized AML treatment on a risk stratification basis in younger adults. However
there is still an unmet medical need for effective therapies in AML since disease relapses in almost half of adult patients
becoming refractory to salvage therapy. Improvements in the understanding of molecular biology of cancer and identification of
recurrent mutations in AML provide opportunities to develop targeted therapies and improve the clinical outcome. In the
spectrum of identified gene mutations, primarily targetable lesions are gain of function mutations of tyrosine kinases FLT3,
JAK2 and cKIT for which specific, dual and multi-targeted small molecule inhibitors have been developed. A number of
targeted compounds such as sorafenib, quizartinib, lestaurtinib, midostaurin, pacritinib, PLX3397 and CCT137690 are in
clinical development. For loss-of-function gene mutations, which are mostly biomarkers of favorable prognosis, combined
therapeutic approaches can maximize the therapeutic efficacy of conventional therapy. Apart from mutated gene products,
proteins aberrantly overexpressed in AML appear to be clinically significant therapeutic targets. Such a molecule for which
targeted inhibitors are currently in clinical development is PLK1. We review characteristic gene mutations, discuss their
biological functions and clinical significance and present small molecule compounds in clinical development, which are
expected to have a role in treating AML subtypes with characteristic molecular alterations. (AJBR1212005).
Keywords: Acute myeloid leukemia, targeted therapy, mutation, FLT3, NPM1, CEBPA, JAK2
Address all correspondence to:
Dr. Eleftheria Hatzimichael
Academic Department of Haematology
University Hospital of Ioannina
St. Niarchou Av, 45110 Ioannina, Greece.
Tel/Fax: +302651099615
E-mail: ehatzim@cc.uoi.gr; eleftheria.chatzimichail@jefferson.edu
| AJBR Copyright © 2011-present, All rights reserved. Published by e-Century Publishing Corporation, Madison, WI 53711, USA |
 |  |  |  |  |  |  |