TAL1 cooperates with PI3K/AKT pathway activation in T-cell acute lymphoblastic leukemia.

TAL1 is ectopically expressed in about 30% of T-cell acute lymphoblastic leukemia (T-ALL) due to chromosomal rearrangements leading to the STIL-TAL1 fusion genes or due to non-coding mutations leading to a de novo enhancer driving TAL1 expression. Analysis of sequence data from T-ALL cases demonstrates a significant association between TAL1 expression and activating mutations of the PI3K-AKT pathway. We investigated the oncogenic function of TAL1 and the possible cooperation with PI3K-AKT pathway activation using isogenic pro-T-cell cultures ex vivo and in vivo leukemia models. We found that TAL1 on its own suppressed T-cell growth, in part by affecting apoptosis genes, while the combination with AKT pathway activation reduced apoptosis and was strongly driving cell proliferation ex vivo and leukemia development in vivo. As a consequence, we found that TAL1+AKTE17K transformed cells are more sensitive to PI3K-AKT pathway inhibition compared to AKTE17K transformed cells, related to the negative effect of TAL1 in the absence of activated PI3K-AKT signaling. We also found that both TAL1 and PI3K-AKT signaling increased the DNA-repair signature in T cells resulting in synergy between PARP and PI3K-AKT pathway inhibition. In conclusion, we have developed a novel mouse model for TAL1+AKTE17K driven T-ALL development and have identified a vulnerability of these leukemia cells to PI3K-AKT and PARP inhibitors.

Successful Treatment of Very Severe Sinusoidal Obstruction Syndrome After Gemtuzumab Ozogamicin With Transjugular Intrahepatic Portosystemic Shunt, Defibrotide, and High-Dose Corticosteroids: A Case Report.

Sinusoidal obstruction syndrome (SOS) is a rare but potentially life-threatening complication, usually described in the setting of hematopoietic stem cell transplantation (HSCT). The very severe forms have a high mortality rate (>80%) and need fast recognition and urgent treatment. In this case report, we describe a unique and successful treatment strategy. We present a 27-year-old patient with newly diagnosed CD33+ acute myeloid leukemia (AML). She was treated with induction chemotherapy (7+3 regimen) and gemtuzumab ozogamicin (GO). In the absence of other major risk factors, she developed a very severe SOS with multiple organ failure. She was successfully treated with the urgent insertion of a transjugular intrahepatic portosystemic shunt (TIPS), defibrotide, and high-dose corticosteroids. This case of successful treatment for very severe SOS supports a combination strategy involving the immediate mechanical reduction of portal hypertension through TIPS and drug-mediated inhibition of microvascular thrombosis. Furthermore, this case shows the need for an improved prevention strategy, including the identification of additional risk factors and biomarkers.