Bone marrow mesenchymal stem cells from infants with MLL-AF4+ acute leukemia harbor and express the MLL-AF4 fusion gene

Abstract

MLL-AF4 fusion is a hallmark genetic abnormality in infant B-acute lymphoblastic leukemia (B-ALL) known to arise in utero. The cellular origin of leukemic fusion genes during human development is difficult to ascertain. The bone marrow (BM) microenvironment plays an important role in the pathogenesis of several hematological malignances. BM mesenchymal stem cells (BM-MSC) from 38 children diagnosed with cytogenetically different acute leukemias were screened for leukemic fusion genes. Fusion genes were absent in BM-MSCs of childhood leukemias carrying TEL-AML1, BCR-ABL, AML1-ETO, MLL-AF9, MLL-AF10, MLL-ENL or hyperdiploidy. However, MLL-AF4 was detected and expressed in BM-MSCs from all cases of MLL-AF4+ B-ALL. Unlike leukemic blasts, MLL-AF4+ BM-MSCs did not display monoclonal Ig gene rearrangements. Endogenous or ectopic expression of MLL-AF4 exerted no effect on MSC culture homeostasis. These findings suggest that MSCs may be in part tumor-related, highlighting an unrecognized role of the BM milieu on the pathogenesis of MLL-AF4+ B-ALL. MLL-AF4 itself is not sufficient for MSC transformation and the expression of MLL-AF4 in MSCs is compatible with a mesenchymal phenotype, suggesting a differential impact in the hematopoietic system and mesenchyme. The absence of monoclonal rearrangements in MLL-AF4+ BM-MSCs precludes the possibility of cellular plasticity or de-differentiation of B-ALL blasts and suggests that MLL-AF4 might arise in a population of prehematopoietic precursors.

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

“…Most of our understanding of transformation by MLL-AF4 has come from murine models [2][3][4]26,27 and human stem cell systems. 1,[28][29][30][31][32][33] These have provided important insights into the likely mode of action of MLL-AF4, but the in vivo leukemias produced in these studies do not recapitulate the actual human disease phenotype and latency, and therefore MLL-AF4 leukemogenesis remains particularly difficult to model. This suggests that in order to develop a bona fide MLL-AF4 model by which to further understand the disease pathogenesis and to screen novel small-molecule compounds, additional oncogenic events such as FLT3 constitutive activation 8 or the derivative AF4-MLL seem to be required to develop ALL.…”

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

“…87 Fusion genes were absent in BM MSCs of childhood leukemias carrying TEL-AML1, BCR-ABL, AML1-ETO, MLL-AF9, MLL-AF10, MLL-ENL or hyperdiploidy. However, MLL-AF4 was detected by fluorescence in situ hybridization and inverse PCR (Figure 3a, Table 2) and expressed by real-time PCR (Figure 3b) in BM MSCs from all cases of MLL-AF4 þ B-ALL.…”

“…However, MLL-AF4 was detected by fluorescence in situ hybridization and inverse PCR (Figure 3a, Table 2) and expressed by real-time PCR (Figure 3b) in BM MSCs from all cases of MLL-AF4 þ B-ALL. 87,88 All MLL-AF4 þ MSCs were consistently euploid, precluding the possibility of cell fusion between a MSC and a leukemic blast. 87 Importantly, monoclonal VD(J)H immunoglobulin gene rearrangements were performed.…”

“…87,88 All MLL-AF4 þ MSCs were consistently euploid, precluding the possibility of cell fusion between a MSC and a leukemic blast. 87 Importantly, monoclonal VD(J)H immunoglobulin gene rearrangements were performed. Whereas monoclonal immunoglobulin gene rearrangements were consistently detected in MLL-AF4 þ leukemic blasts, no monoclonal rearrangements could be detected in BM MSCs from any MLL-AF4 þ B-ALL patient, ruling out potential contamination of the MSC cultures by leukemic cells and suggesting a close early developmental relationship between MSCs and the leukemic blasts rather than plasticity or dedifferentiation of B-ALL blasts.…”

Les cellules souches mésenchymateuses

“…De plus, on ne peut exclure que des altérations géniques de CSM puissent favoriser le développement de certains cancers comme cela a été suggéré pour les cellules stromales composant la niche hématopoïétique dans le cas de certaines leucémies [30][31][32]. Ce champ d'investigation très actif aujourd'hui permettra d'envisager les potentialités et les écueils de l'utilisation des CSM dans le traitement des cancers, mais aussi le rôle des CSM endogènes dans le développement tumoral.…”