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Linköping University Medical Dissertations No. 1160

Live and Let Die

Critical regulation of survival in normal and malignant

hematopoietic stem and progenitor cells

Pernilla Eliasson

Experimental Hematology unit

Department of Clinical and Experimental Medicine

Faculty of Health Sciences

SE-581 85 Linköping, Sweden

Linköping 2009

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Copyright © Pernilla Eliasson, 2009

Cover picture is an illustration made by the author of a hematopoietic stem cell in the
trabecular bone of the bone marrow

Experimental Hematology unit
Department of Clinical and Experimental Medicine
Faculty of Health Sciences
SE-581 85 Linköping, Sweden

Printed by LiU-tryck, Linköping, Sweden, 2009

Published articles have been reprinted with the permission from respective copyright

During the course of the research underlying this thesis, Pernilla Eliasson was enrolled
in Forum Scientium, a multidisciplinary doctoral programme at Linköping University,

ISBN 978-91-7393-470-1
ISSN 0345-0082

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AML is an aggressive malignancy with short survival rates if not treated. AML is

thought to arise in leukemic stem cells (LSCs) and is characterized by aberrant

proliferation of myeloid progenitor cells coupled to a partial block in differentiation.

This in turn causes bleeding, anemia and immune suppression due to the decreased

number of mature functional leukocytes, erythrocytes, and thrombocytes. The overall

incidence is 3.4 cases per 100 000 inhabitants, but increases significantly with age

(Tallman et al., 2005). Poor prognosis is often associated to AML due to therapy-

induced mortality or resistance to chemotherapy (reviewed in (Weisberg et al.,

2009)). As described above, deregulation of tyrosine kinases in particular FLT3, has

for the last decade been implicated in the molecular pathology of AML.

The current treatment of AML is chemotherapy and BMT. Growing insight in specific

pathogenic molecular mechanism has led to the development of novel therapeutic

drugs, such as FLT3 inhibitors, inhibitors of bone marrow niche targets and BH3

mimetic drugs.

FLT3 inhibitors
The high frequency of FLT3 mutations associated with a poor prognosis has made

FLT3 an interesting molecular target for treatment of AML. To date, many tyrosine

kinase inhibitors have been developed where some are in clinical trials. Although they

all interact with and inhibit FLT3 signaling, no FLT3 kinase-specific inhibitor has been

developed. FLT3-inhibitors often recognize other RTKs such as PDGFR, VEGFR, and c-

KIT. After the success of the tyrosine inhibitor imatinib (Glivec; Novartis) used in

treatment of chronic myeloid leukemia (CML) by inhibiting the kinase activity in the

fusion protein BCR/ABL, there has been a massive struggle to find an inhibitor as

effective for treatment of AML. It must however be noticed that BCR/ABL might be

the only molecular abnormality leading to the development of CML in contrast to

AML, which is a multi-mutational leukemia, where constitutively active FLT3 is only

one of many genetic alterations. The molecular mechanism for these small molecule

kinase inhibitors is to mimic the adenosine structure and compete with ATP for

binding to the ATP-binding pocket in the kinase domain. The first report that FLT3 is a

potential therapeutic target for AML used the FLT3 inhibitor AG1295. AG1295 inhibits

FLT3-ITD and wild type FLT3 and noticeably reduced the number of AML blasts in

vitro (Levis et al., 2001). Because of its low bioavailability and low potency, AG1295

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cannot be used clinically but is used in research to study cellular and molecular

mechanisms influenced by FLT3-inhibition. Since then, several FLT3 inhibitors, such as

SU11248, CEP701, PKC412, and MLN-518, have been discovered and investigated.

PKC412 was originally developed as an inhibitor against protein kinase C, but was

shown to be a more powerful inhibitor of FLT3 kinase activity. Through its inhibition

of FLT3-ITD and FLT3-TKD it caused cell cycle arrest and apoptosis in leukemic cells

(Weisberg et al., 2002). In addition, administration of PKC412 to mice with FLT3-ITD-

induced leukemia showed prolonged survival. In a phase 2 study, PKC412 reduced

peripheral blast count to 50% or less in 14 of 20 patients, whereas bone marrow blast

counts were reduced to 50% in only 6 patients (Stone et al., 2005). This low response

in reduction of bone marrow blasts is generally described for all FLT3 inhibitors used

in clinical trials so far. In addition, other clinical problems, such as maintaining plasma

concentrations of the drug and avoiding drug toxicity, need to be resolved before

tyrosine inhibitors can be used in treatment of AML. The acquisition of additional

mutations in the kinase domain inhibiting drug binding, increased expression of FLT3,

and the activation of compensatory signaling pathways for survival are potential

mechanisms by with the drug response can be reduced. The rapid developed

resistance to tyrosine inhibitors as sole therapeutic agents has lead to clinical trials of

FLT3 inhibitors in combination with conventional cytotoxic therapy. Hopefully, this

would target the pathologic mechanism of AML while avoiding some toxicity from

chemotherapy, as well as resistance to kinase inhibitors (reviewed in (Knapper,


Therapies that targets the leukemic stem cell niche
The high incidence of relapse in AML is thought to be explained by leukemic stem

cells (LSCs) escaping conventional chemotherapy. LSCs have self-renewal capacities

and the ability to give rise to more mature hematopoietic cells (Somervaille and

Cleary, 2006). A high percentage of leukemic stem cells at the time of diagnosis often

reflect a number of remaining chemotherapy-resistant cells associated with poor

survival (van Rhenen et al., 2005). If FLT3-ITD mutations occur in leukemic stem cells

remains to be investigated. Data regarding the FLT3-ITD expression on AML blasts at

the time for diagnosis and relapse provide useful information for this question. In

addition, the mutant-to-wild type ratio might provide meaningful information to

when the FLT3-ITD mutation occurs. Some studies have shown that patients

diagnosed with FLT3-ITD all showed FLT3-ITD expressing blast cells at relapse,

whereas others have shown the mutations were lost at relapse (reviewed in (Levis

and Small, 2003)). A loss of FLT3-

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Stat5b for Flt3-dependent signaling. The Journal of experimental medicine

Zhang W, Konopleva M, Ruvolo VR, McQueen T, Evans RL, Bornmann WG, McCubrey J,
Cortes J, Andreeff M. 2008. Sorafenib induces apoptosis of AML cells via Bim-
mediated activation of the intrinsic apoptotic pathway. Leukemia 22(4):808-818.

Zhou S, Schuetz JD, Bunting KD, Colapietro AM, Sampath J, Morris JJ, Lagutina I, Grosveld GC,
Osawa M, Nakauchi H, Sorrentino BP. 2001. The ABC transporter Bcrp1/ABCG2 is
expressed in a wide variety of stem cells and is a molecular determinant of the side-
population phenotype. Nature medicine 7(9):1028-1034.

Zong WX, Lindsten T, Ross AJ, MacGregor GR, Thompson CB. 2001. BH3-only proteins that
bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax
and Bak. Genes & development 15(12):1481-1486.

Zou H, Henzel WJ, Liu X, Lutschg A, Wang X. 1997. Apaf-1, a human protein homologous to C.
elegans CED-4, participates in cytochrome c-dependent activation of caspase-3. Cell

Zou H, Li Y, Liu X, Wang X. 1999. An APAF-1.cytochrome c multimeric complex is a functional
apoptosome that activates procaspase-9. The Journal of biological chemistry

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