The composition of leukapheresis products impacts on the hematopoietic recovery after autologous transplantation independently of the mobilization regimen

Menéndez, Pablo; Caballero, Marı́a Dolores; Prósper, Felipe; Cañizo, M.C. del; Pérez-Simón, Josè Antonio; Mateos, María Victoria; Nieto, María Jesús Rodríguez; Corral, Mercedes; Romero, Martha Lacayo; Garcı́a-Conde, J; Montalbán, María Ángeles; Miguel, Jesús F. San; Órfão, Alberto

doi:10.1046/j.1537-2995.2002.00190.x

Cited by 37 publications

(22 citation statements)

References 40 publications

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“…The parameters were considered either as continuous or as categorical variables and only those reaching a P value o0.1 in the respective univariate analysis were included. 24,25 All P values were considered significant when o0.05. These analyses were performed using the SPSS 15.0 statistical software package (SPSS Inc., Chicago, IL, USA).…”

Section: Discussionmentioning

confidence: 99%

Prognostic significance of FLT3 mutational status and expression levels in MLL-AF4+ and MLL-germline acute lymphoblastic leukemia

et al. 2012

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There is barely any information about the prognostic significance of FLT3 expression and mutational status in cytogenetically distinct subgroups of acute lymphoblastic leukemia (ALL). We analyzed the presence of FLT3-tyrosine kinase domain (TKD) and FLT3-internal tandem duplication (ITD) mutations as well as FLT3 expression levels in 54 newly diagnosed patients with B-ALL (n ¼ 49) or T-ALL (n ¼ 5). All B/T-ALL samples tested negative for the presence of FLT3-TKD or FLT3-ITD. None of the T-ALL and E2A-PBX1 þ B-ALL overexpressed FLT3. In contrast, mainly MLL-AF4 þ B-ALL but also ETV6-RUNX1 þ , BCR-ABL þ or B-ALL displaying normal cytogenetics exhibited significantly higher FLT3 expression levels than normal bone marrow, supporting that aberrantly increased transcription of FLT3, rather than activating FLT3 mutations, contributes to the pathogenesis of these B-ALL. Using the median FLT3 expression as cut-off value we found that high-level FLT3 expression is associated with an extremely poor 1-year overall survival (OS; 0 vs 71%; P ¼ 0.002) and disease-free survival (DFS; 0 vs 43%; P ¼ 0.03) in MLL-AF4 þ B-ALL but not in MLL-germline B-ALL. Cox regression analysis with OS/DFS as end points showed that age414 years and high-level FLT3 expression were independent prognostic factors when all ALL patients were analyzed together. Importantly, when the MLL-AF4 þ B-ALL subgroup was analyzed separately, high-level FLT3 expression was the only independent prognostic factor for OS and treatment outcome. These findings indicate that high FLT3 expression identifies MLL-AF4 þ ALL patients at very high risk of treatment failure and poor survival, emphasizing the value of ongoing/future clinical trials for FLT3 inhibitors.

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Section: Discussionmentioning

confidence: 99%

Prognostic significance of FLT3 mutational status and expression levels in MLL-AF4+ and MLL-germline acute lymphoblastic leukemia

et al. 2012

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“…Statistical comparisons were performed with a paired Student's t test. Statistical significance was defined as a P value <0.05 [4,5,27,28].…”

Section: Discussionmentioning

confidence: 99%

The ROCK Inhibitor Y-27632 Negatively Affects the Expansion/Survival of Both Fresh and Cryopreserved Cord Blood-Derived CD34+ Hematopoietic Progenitor Cells

Bueno

Montes

Menéndez

2010

Stem Cell Rev and Rep

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Cord blood (CB) is an unlimited source of hematopoietic stem and progenitor cells (HSPC). The use of cryopreserved CB-derived CD34+ HSPCs is successful in children and usually leads to rapid hematopoietic recovery upon transplantation. However, current methods for ex vivo expansion of HSPCs still result in a loss of multilineage differentiation potential and current freeze-thawing protocols result in significant cell death and loss of CD34+ HSPCs. The major cause for the loss of viability after slow freezing is apoptosis induced directly by cryoinjury. Very recent reports have demonstrated that Y-27632, a selective and robust ROCK inhibitor is a potent inhibitor of the apoptosis and is efficient in enhancing the post-thaw survival and recovery of different human stem cells including human embryos, hESCs, induced pluripotent stem cells and mesenchymal stem cells. Here, we analyzed the effect of such an inhibitor in CB-derived CD34+ HSPCs. CB-derived CD34+ HSPCs were MACS-isolated and treated with or without 10 microM of Y-27632. The effect of Y-27632 on culture homeostasis was determined in both fresh and cryopreserved CB-derived CD34+ HSPCs. Our results indicate that the Y-27632 not only dramatically inhibits cell expansion of both fresh and cryopreserved CD34+ HSPCs but also impairs survival/recovery of CD34+ HSPCs upon thawing regardless whether Y-27632 is added to both the cryopreservation and the expansion media and or just to the expansion culture medium with or without hematopoietic cytokines. This study identifies for the first time a detrimental effect of Y-27632 on the expansion and survival of both fresh and cryopreserved CB-derived CD34+ HSPCs, suggesting that Y-27632 may have a differential impact on distinct lineage/tissue-specific stem cells. Our data suggest different functions of Y-27632 on human stem cells growing in suspension versus those growing attached to either treated tissue culture plastic or extracellular matrix. We discourage any clinical application of Y-27632 in potential technical developments aimed at improving cryopreservation procedures of CB-derived cells and/or in vitro expansion of HSPCs without spontaneous differentiation.

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“…We therefore addressed whether pDC CD34 þ precursors coexpress NG2. Interestingly, we found that 12.2% of the pDC precursors (CD34 þ /CD45 þ /CD38 þ / CD123 high /HLADR þ ) [65][66][67] readily coexpress NG2 (Figure 2c). This suggests that, regardless of the status of the MLL locus, the NG2 antigen may be expressed in pDC leukemias if the leukomogenesis process is initially triggered in a pDC CD34 þ precursor readily expressing NG2, which might act as a leukemic-initiating cell.…”

Section: Environmental Exposures and Delayed Infection Early In Life mentioning

confidence: 95%

Insights into the cellular origin and etiology of the infant pro-B acute lymphoblastic leukemia with MLL-AF4 rearrangement

et al. 2010

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Infant acute lymphoblastic leukemia (ALL) involving mixedlineage leukemia (MLL) fusions has attracted a huge interest in basic and clinical research because of its prenatal origin, mixed-lineage phenotype, dismal prognosis and extremely short latency. Over 90% of infant ALLs are pro-B ALL harboring the leukemic fusion MLL-AF4. Despite the fact that major achievements have provided a better understanding about the etiology of infant MLL-AF4 þ ALL over the last two decades, key questions remain unanswered. Epidemiological and genetic studies suggest that the in utero origin of MLL rearrangements in infant leukemia may be the result of prenatal exposure to genotoxic compounds. In fact, chronic exposure of human embryonic stem cells (hESCs) to etoposide induces MLL rearrangements and makes hESC more prone to acquire subsequent chromosomal abnormalities than postnatal CD34 þ cells, linking embryonic exposure to topoisomerase II inhibitors to genomic instability and MLL rearrangements. Unfortunately, very little is known about the nature of the target cell for transformation. Neuron-glial antigen 2 expression was initially claimed to be specifically associated with MLL rearrangements and was recently shown to be readily expressed in CD34 þ CD38 þ , but not CD34 þ CD38À cells suggesting that progenitors rather than stem cells may be the target cell for transformation. Importantly, the recent findings showing that MLL-AF4 rearrangement is present and expressed in mesenchymal stem cells from infant patients with MLLAF4 þ ALL challenged our current view of the etiology and cellular origin of this leukemia. It becomes therefore crucial to determine where the leukemia relapses come from and how the tumorstroma relationship is defined at the molecular level. Finally, MLL-AF4 leukemogenesis has been particularly difficult to model and bona fide MLL-AF4 disease models do not exist so far. It is likely that the current disease models are missing some essential ingredients of leukemogenesis in the human embryo/ fetus. We thus propose modeling MLL-AF4 þ infant pro-B ALL using prenatal hESCs.

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The composition of leukapheresis products impacts on the hematopoietic recovery after autologous transplantation independently of the mobilization regimen

Cited by 37 publications

References 40 publications

Prognostic significance of FLT3 mutational status and expression levels in MLL-AF4+ and MLL-germline acute lymphoblastic leukemia

Prognostic significance of FLT3 mutational status and expression levels in MLL-AF4+ and MLL-germline acute lymphoblastic leukemia

The ROCK Inhibitor Y-27632 Negatively Affects the Expansion/Survival of Both Fresh and Cryopreserved Cord Blood-Derived CD34+ Hematopoietic Progenitor Cells

Insights into the cellular origin and etiology of the infant pro-B acute lymphoblastic leukemia with MLL-AF4 rearrangement

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