Mutations of the Smad4 gene in acute myelogeneous leukemia and their functional implications in leukemogenesis

Abstract

The Smad family proteins are critical components of the transforming growth factor (TGF)-b signaling pathway. TGF-b is a multipotent cytokine that elicits many biological functions. In particular, TGF-b exhibits e ects on the cell cycle manifested by G1-phase arrest, di erentiation, or apoptosis of several target cells, suggesting that disruption of TGF-b signaling pathway could be involved in cancer formation. Here we show one missense mutation of the Smad4 gene in the MH1 domain (P102L) and one frame shift mutation resulting in termination in the MH2 domain (D(483 ± 552)) in acute myelogeneous leukemia. Both of the mutated Smad4 proteins lack transcriptional activities. Concomitant expression of the P102L mutant with wild-type Smad4 inactivates wild-type Smad4 through inhibiting its DNA-binding ability. The D(483 ± 552) mutant blocks nuclear translocation of wild-type Smad4 and thus disrupts TGF-b signaling. This is the ®rst report showing that mutations in the Smad4 gene are associated with the pathogenesis of acute myelogeneous leukemia and the obtained results should provide useful insights into the mechanism whereby disruption of TGF-b signaling pathway could lead to acute myelogeneous leukemia. Oncogene (2001) 20, 88 ± 96.

Cooperating gene mutations in acute myeloid leukemia: a review of the literature

“…132 Some monoallelic mutations may act in a dominant-negative manner through inhibition of the effects the remaining WT AML1. This hypothesis was confirmed by Osato et al and Imai et al, 124,126 who demonstrated that some AML1 gene missense mutation cotransfected with WT AML1 abolished transactivation of the M-CSF receptor promoter. Moreover, Imai et al 126 demonstrated that this dominant-negative effect was due to the fact that the mutated protein did not bind DNA but had enhanced capacity to bind CBFb and, by sequestering it, inhibited action of WT AML1, as observed for chimeric products of t(3;21) or t(8;21) translocations.…”

“…122,123 Other mechanisms of AML1 inactivation have been reported in hematological malignancies, through point mutations, in AML and in MDS. [124][125][126][127][128][129] Both germ-line and acquired AML1 mutations have been reported in hematological malignancies. Germ-line mutations of the AML1 gene have initially been reported by Song et al in very rare cases of familial platelet disorder with predisposition to AML (FPD/AML).…”

Amplification of AML1 gene is present in childhood acute lymphoblastic leukemia but not in adult, and is not associated with AML1 gene mutation

“…He remains in continuous remission with maintenance chemotherapy 10 months after diagnosis. The karyotype was: 46,XY,add(1)(q25),add(21)(q21) [6]/46, XY [14]. FISH analysis did not reveal ETV6/AML1 fusion, but an AML1 gene amplification with eight copies on interphase cells.…”

AML1/Runx1 rescues Notch1-null mutation-induced deficiency of para-aortic splanchnopleural hematopoiesis

“…The DNA-binding ability is severely impaired in R139G, although the ability to heterodimerize with CBF␤/PEBP2␤ is spared. 21 This mutant could not restore hematopoiesis. These results suggest that, in the presence of an intact Runt domain, the transcriptional activating function is necessary and sufficient for Runx1 to rescue the hematopoietic defect of Notch1-null mice in the P-Sp culture system, while the transcriptional repressing function is dispensable.…”