**1. Introduction**

298 Advances in Hematopoietic Stem Cell Research

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Kurosaki T. (2008). Erk kinases link pre-B cell receptor signaling to transcriptional events required for early B cell expansion. *Immunity*, Vol.28, No.4, (April 2008), pp. Mobilized peripheral blood stem cells (MPBSC) have nearly replaced bone marrow (BM). So, they become the primary source of hematopoietic grafts especially for patients with hematological malignancies undergoing aggressive myelosuppressive or myeloablative chemotherapy. It allows faster engraftment and equivalent disease-free survival compared with bone marrow cells [Siena S et al, 2000; To LB et al, 1997; Roberto M. Lemoli and Alessandra D'Addio, 2008].

Some reports suggested that hematopoietic stem cell mobilization involves a complex interplay between adhesion molecules, cytokines, proteolytic enzymes such as MMP-9 and MMP-2, stromal cells and chemokines among them (e.g,; SDF-1/CXCR4) play a central role [Roberto M. Lemoli and Alessandra D'Addio, 2008; Tsevee Lapidot and Isabelle Petit, 2002]. It has been reported that increased secretion of SDF-1 downmodulates CXCR4 on CD34+ cells, thus preventing the homing of hematopoietic progenitors to the bone marrow [Signoret N et al, 1997]. Moreover, Dlubek D et al, have observed a negative correlation between mobilization capacity and a reduced expression of CXCR4 on mobilized HPC CD34+ in the leukapheresis product [Dlubek D et al, 2006].

These data suggested a central role for CXCR4 and SDF-1 on mobilization of hematopoietic stem cell as well as their homing to the bone marrow [Dlubek D et al, 2006].

The reason for poor mobilization of hematopoietic stem cells that occur in many donors or patients is fully recognized and patients' characteristics (age, BMI, mobilization regimen, diagnosis and clinical status or ulterior therapy) did not explain the whole thing.

Benboubker and his colleagues identified an association of a polymorphism in the SDF-1 gene, designated as SDF1-3'A, with the rate of mobilization of HPCs CD34+ into peripheral blood [Benboubker L et al, 2001]. Hence, we hypothesized that individual genetic factors might explain, at least in part, this variability and that polymorphism analysis can be used to anticipate CD34+ cells mobilization.

Distribution of SDF1-3'A, GNB3 C825T and MMP-9 C-1562T Polymorphisms

Total <2x10e6 CD34+/kg

Age (years) Median 40.58 33.25

lymphoma) 25 60

Hodgkin's Disease 63 14 49 Multiple Myeloma 87 12 77

leukemia) 15 7 8 *Prior radiotherapy* 62 19 23

< 1 month 121 -

rituximab DSHAP 59 -

(Granocyte®) 80 filgrastim (Neupogen®) 75 - G/C [endoxan+ G-CSF] 95 -

Range 12-64

Lymphoma <sup>80</sup>

lymphoma) <sup>1</sup>

lymphoma) <sup>4</sup>

*Prior chemotherapy* 250

1 to 2 months 20 2 to 3 months 4 > 3 months 5

rituximab CHOP 2 ICE/ RICE 21 Others 168

*time from last chemotherapy to* 

NHL (non Hodgkin's

Diffuse large Cell

ML (mantle Cell

FL(follicular

AML (acute myeloid

*mobilization* 

*Chemomobilization*  Rituximab ESHAP/

*Mobilization regimen*  growth factor only Lenograstim

*Diagnosis* 

in HSC CD34+ from Peripheral Blood of Patients with Hematological Malignancies 301

Male 144 27 117 NS 24 6 11 Female 106 26 80 17 6 6 18

Table 1. patients and healthy allogenic PBPC donors charachteristics Abbreviations: G-CSF, granulocyte colony-stimulating factor; G/C, G-CSF- chemotherapy; ICE, ifosfamide, carboplatin, etoposide; ESHAP/DHAP, etoposide, cytarabine, methylprednisolone,

>2x10e6 CD34+/ kg

PATIENTS PBSC DONORS

p Total

(12-63)

<3x106 CD34/k g

32.25 (15-57)

≥3x106 CD34/k g

> 33.5 (12-63)

So, identifying SNPs predictive of poor or good response to G-CSF or any mobilization regimen, in terms of number of CD34+ cells mobilized, might be useful in discussing the possibility of using a different mobilizing agent or a different source of CD34+ cells for auto-HSCT and allo-HSCT.

In this issue, we proposed to study the distribution of three genetic polymorphisms: SDF1- 3'A, MMP-9 C-1562T and GNB3 C825T in Tunisian patients with malignant hematological diseases who underwent stem cell mobilization for autologous transplantation compared to a group of healthy allogenic PBPC donors.
