Imatinib mesylate can help to direct natural immunity toward an anti-leukemic reactivity by acting on the bone marrow microenvironment.

2012·0.29 MB·English

by  Poggi, Alessandro

OncoImmunology1:2,214–216;March/April2012;G2012LandesBioscience
Imatinib mesylate can help to direct natural
immunity toward an anti-leukemic reactivity by
acting on the bone marrow microenvironment
Alessandro Poggi1 and Maria Raffaella Zocchi2
1UnitofMolecularOncologyandAngiogenesis;SanMartinoHospital-NationalInstituteforCancerResearch;UniversityofGenoa;Genoa,Italy;2DivisionofImmunology;
TransplantsandInfectiousDiseases;ScientificInstituteSanRaffaele;Milan,Italy
Keywords: chronic myelogenous leukemia, B1 cells, SDF-1 BAFF, bone morphogenetic proteins
We discuss our recent findings on the increase, in chronic myeloid leukemia patients treated with imatinib, of B1
lymphocytes producing IgM anti-O-linked sugars expressed by leukemic cells, paralleled by increased B-stimulating
cytokines. We propose that one important effect of imatinib treatment is due to the remodelling of bone marrow
microenvironment.
© 2012 Landes Bioscience.
In the last years, tyrosine kinases have microenvironmental factors,2 pointing to the so called “natural antibodies,” that are
become the major targets of anti-cancer the possibility that imatinib action is not indeedproducedbyCD5+Blymphocytes,
drugs. In particular, imatinib mesylate, an limited to the leukemic cell population. also known as B1 lymphocytes, and in
ATP competitive inhibitor of the consti- There is increasing evidence that the healthy donors mainly involved in anti-
tutively activated ABLD1 tyrosoine kin asne of orespontset oimdatinibimsesylatetisarlsoliinkbed buacteriatl reseponse.s.5,6
the BCR-ABL oncoprotein, is approved to the immune system with production of Thus, administration of imatinib mesy-
for the treatment of chronic myelogenous antineoplastic cytokines and activation of late can actually contribute to an “immu-
leukemia (CML) in chronic phase; recent immune cell function by creating a bridge nologic bridge,” that functions exploiting
updates of the phase 3 International between innate and adaptive immunity.3 natural antibodies to activate an anti-
Randomized Study of Interferon and In a recent paper,4 we reported that in tumor reaction. How does it happen and
STI571 (IRIS) trial have confirmed both CML patients responding to imatinib what is the mechanism that leads to the
long-term efficacy and safety of the treat- treatmentclinicalandcytogeneticresponse stimulation of B1 cells? In the bone
ment, with an estimated overall survival is paralleled or preceded by early cytolo- marrow of responder patients, the pro-
rate of 86%.1 However, resistance to gical,phenotypicandmolecularchangesin duction of the stromal-derived factor-1
imatinib can occur, or develop during the bone marrow, involving the B cell (SDF-1) and of the B lymphocyte activ-
treatment, leading to the failure of the compartment, that are not detectable in ating factor of the tumor necrosis factor
therapy and highlighting the need of early non responder patients. In particular, a family (BAFF), both involved in normal
markers of clinical response in order to raise in CD20+ B lymphocytes, coexpres- B cell development and maturation,7 is
addressalternativetreatments.Ofcourse,a sing CD5 and bearing surface (s)IgM, is induced by imatinib, at variance with non
deeper understanding of the mechanisms evidenced as early as 3 mo after the responder patients. Thus, imatinib seems
underlyingthefunctionofthedrugwould beginning of therapy and persists up to to be capable of modulating the bone
be of help. Resistance is usually due to 6–9 mo. This population of cells is marrowmicroenvironmentleadingtocon-
point mutations in the BCR-ABL ATP- antibody-secreting, as an increase of IgM ditions favorable to B cell differentiation.
binding site, that impede the binding of ismeasuredinthebonemarrowplasmaof It is tempting to speculate that imatinib
imatinib.1,2 Nevertheless, other mechan- responder patients. Of note, this IgM treatment is able to “reset” the bone
isms have been reported, such as BCR- fraction contains antibodies which are marrowmicroenvironment,involvingstro-
ABL gene amplification, aberrations in reactive with O-linked olygosaccharides mal and/or endothelial cells possibly res-
other oncogenic signaling pathways, and expressedby leukemic cells and capable to ponsibleforSDF-1andBAFFproduction,
the persistence of leukemic stem cells.2 kill them by a complement-independent that, in turn, would enhance the B cell
Extrinsic factors have also been hypothe- mechanism. Such antibodies, described in compartment. This might be due to the
sized, including multidrug resistance and the sera of solid cancer patients, resemble therapeutic effects exerted by imatinib on
Correspondenceto:AlessandroPoggiandMariaRaffaellaZocchi;Email:[email protected]@hsr.it
Submitted:09/15/11;Accepted:09/15/11
http://dx.doi.org/10.4161/onci.1.2.18112
214 OncoImmunology Volume1Issue2
AUTHOR'SVIEW
© 2012 Landes Bioscience.
Figure1.Modelforanadditionalmechanismofactionofimatinibmesylate.Imatinibmesylatewouldcontributetotherenewalofthewholebone
marrowmicroenvironment,duetothe“normalization”ofhematopoieticprecursors,abletogiverisetohealthybonemarrowstromalcells(BMSC),
fibroblasts(FB),osteoblasts(OB)andendothelialcells(EC),thusrebuildingtheBM“niche.”Normalproductionofbonemorphogeneticproteins(BMP),
Blymphocyteactivatingfactorofthetumornecrosisfactorfamily(BAFF)andstromalderivedfactor-1(SDF-1)bynormalBMSC,FB,EC,wouldremodel
themicroenvironmentandparticipateintothedevelopmentoftheBcellpopulationproducingtumor-reactiveIgM.
Do not distribute.
the myeloid malignant progenitors,8 that remains to be defined the contribution tumor-reactive IgM, through theenhanced
would be substituted by normal precur- given in vivo by the CD20+CD5+ IgM- production of BMP, BAFF and SDF-1
sors, capable of repopulating the bone secreting B cells population observed in (Fig.1). These changes are indeed docu-
marrow with normal stromal as well as responder patients to the clearance of mented in the bone marrow and sera of
normal myeloid cells. This hypothesis leukemic cells, they would represent the responder patients and transiently detect-
seems to be also supported by our finding enhancement of B cell maturation and able for a period of up to 6–9 mo, by
that in the bone marrow of responder function in a restored bone marrow, which time the resetting process would
patients, transcription of the bone as an early sign of the response to the be concluded, as proved by the stability
morphogenetic proteins (BMP)2 and treatment. of the clinical, cytogenetic and molecular
BMP7, both related to SDF-1 synthesis, We conclude that imatinib mesylate response. As a statistically significant
are increased. Effects of imatinib on the significantly contributes to the renewal of correlation to the clinical, cytogenetic
osteoblastogenesis and bone marrow the whole bone marrow microenviron- and molecular response was found, we
remodelling, mediated by BMP2, have ment, due to a rescue of healthy progeni- propose that the detection of IgM+ B cells
been recently reported;9 moreover, tors, capable of give rise to a normal and the measurement of cytokines in the
BAFF synthesis and release by normal stromalcompartment,composedofstromal bone marrow before and during treat-
myeloid cells has been described.9 cells, fibroblasts, osteoblasts and endo- ment may contribute to the early identi-
Also, SDF-1 has been shown to block thelial cells; this restored microenviron- fication of responder and non responder
colony forming units by both healthy ment would lead to the development of patients, and help in the choice and/or
and CML CD34+ cells.10 Although it the observed B cell population producing design of alternative therapeutic strategies.
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