MLL Gene Rearrangement, Cytogenetic 11q23 Abnormalities, and Expression of the NG2 Molecule in Infant Acute Myeloid Leukemia

Abstract

To study prognostic factors in infant acute myeloid leukemia (AML), we analyzed 44 children treated on Childrens Cancer Group protocols for MLL gene rearrangement by Southern blot, cytogenetic 11q23 abnormalities, and reactivity with monoclonal antibody 7.1. This antibody detects the human homologue of the rat NG2 chondroitin sulfate proteoglycan molecule, which has previously been reported to be expressed on human melanoma. NG2 has been found to be expressed on human leukemic blasts but not on other hematopoietic cells. In childhood AML, NG2 cell surface expression correlated with poor outcome and with some but not all 11q23 rearrangements. In childhood acute lymphoblastic leukemia, NG2 expression correlated with poor outcome and with balanced 11q23 translocations. In this study, 29 of 44 (66%) of infants with AML showed MLL rearrangement and, as expected, this group had a high incidence of French-American-British M4/M5 morphology (22/29). Of the cases tested, 35.1% (13/37) were NG2 positive. All (13/13) NG2-positive cases were rearranged at MLL, whereas only 46% (11/24) of NG2-negative cases had MLL rearrangement. NG2 expression did not correlate with poor outcome (P = .31); there was a trend towards a worse outcome with MLL rearrangement (P = .13). Thus monoclonal antibody 7.1 does not detect all cases of MLL rearrangement in infant AML.

NG2 expression in MLL rearranged acute myeloid leukaemia is restricted to monoblastic cases

“…None of the 28 cases showed 7.1/NG2 expression (range 0±19%), although in two cases the number of positive cells was close to the positivity threshold. These data therefore extend the 100% speci®city of 7.1 described in paediatric AL (Smith et al, 1996;Hilden et al, 1997;Behm et al, 1996b) to adult AML.…”

“…Given the low sensitivity, 7.1 negativity has little value, particularly in AML M1 and M2 cases. Sensitivity amongst FAB monocytic cases is not absolute, varying from 58% (11/19) (Hilden et al, 1997) to 75% (6/8) in the present series. Our data demonstrate clearly that, if 7.1 has a place in AML screening as a means of limiting MLL analysis, its use should be restricted to myelomonoblastic cases.…”

“…Amongst AML M5, NG2 expression was therefore seen in 6/ 8 MLL rearranged but 0/12 MLL germline cases (P<0´001), demonstrating that the positivity was related to MLL rather than monocytic differentiation. In paediatric AML, 24/31 Short Report q 1999 Blackwell Science Ltd, British Journal of Haematology 107: 674±676 (77%) of NG2-positive cases were FAB M4/M5, with the majority of the remaining cases being unclassi®ed (Hilden et al, 1997;Smith et al, 1996). Since, however, the proportion of MLL rearranged M1 or M2 AML is much lower in paediatric than adult AML (3/29 in (Hilden et al, 1997)), the correlation with maturation arrest was easier to identify in adults.…”

“…In paediatric AML, 24/31 Short Report q 1999 Blackwell Science Ltd, British Journal of Haematology 107: 674±676 (77%) of NG2-positive cases were FAB M4/M5, with the majority of the remaining cases being unclassi®ed (Hilden et al, 1997;Smith et al, 1996). Since, however, the proportion of MLL rearranged M1 or M2 AML is much lower in paediatric than adult AML (3/29 in (Hilden et al, 1997)), the correlation with maturation arrest was easier to identify in adults. Comparison of the CD4, CD7, CD13, CD14, CD15, CD33, CD34, HLA-DR, CD11b, CD11c, CD42, CD36 and CD41 immunological markers did not identify any differences in their expression in the 7.1 positive and negative groups (data not shown).…”

CSPG4, a potential therapeutic target, facilitates malignant progression of melanoma

“…It is detected readily in tumors of neuroectodermal origin including oligodendroglioma and glioblastomas (Stallcup and Huang, 2008). CSPG4 expression is detected in a subset of childhood acute lymphoblastic leukemia and acute myeloid leukemia, where its expression correlates with a poorer prognosis, particularly for those patients demonstrating 11q23 translocations (Hilden et al, 1997;Petrovici et al, 2010). CSPG4 is also detected in renal cell carcinomas, chondrosarcomas, and pancreatic cell carcinomas, although studies are needed to identify potential tumor-related functions in those tumors (Campoli et al, 2010;Wang et al, 2010b).…”