T-cell Acute Lymphoblastic Leukemia: A Roadmap to Targeted Therapies

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy characterized by aberrant proliferation of immature thymocytes. Despite an overall survival of 80% in the pediatric setting, 20% of patients with TALL ultimately die from relapsed or refractory disease. Therefore, there is an urgent need for novel therapies. Molecular genetic analyses and sequencing studies have led to the identification of recurrent TALL genetic drivers. This review summarizes the main genetic drivers and targetable lesions of TALL and gives a comprehensive overview of the novel treatments for patients with TALL that are currently under clinical investigation or that are emerging from preclinical research. Significance: TALL is driven by oncogenic transcription factors that act along with secondary acquired mutations. These lesions, together with active signaling pathways, may be targeted by therapeutic agents. Bridging research and clinical practice can accelerate the testing of novel treatments in clinical trials, offering an opportunity for patients with poor outcome.

Advances in the Diagnosis and Treatment of Pediatric Acute Lymphoblastic Leukemia

“…T-ALL represents approximately 12% to 15% of pediatric ALL and is characterized by having an incidence in boys that is two to three times that in girls; a higher proportion of patients with African ancestry, in whom the rate is twice that in patients of European ancestry; high initial WBC counts; and higher frequencies of mediastinal mass and CNS involvement [ 12 , 84 ]. The higher incidence in boys can be partly explained by inactivating mutations or deletions of the tumor suppressor gene PHF6 on chromosome X, which are seen in 16% of pediatric T-ALL cases [ 85 ].…”

Phosphoproteomic profiling of T cell acute lymphoblastic leukemia reveals targetable kinases and combination treatment strategies

“…Milciclib is under clinical investigation for the treatment of thymoma and hepatocellular carcinoma 33 . Currently, clinical studies are investigating other CDKs inhibitors (ribociclib and palbociclib) for the treatment of relapsed T-ALL 12 and milciclib may be an additional treatment option.…”

“…Furthermore, since several studies highlighted a role for LCK in supporting resistance to glucocorticoids in T-ALL 43 , 44 , targeting LCK activation could provide additional benefits to other combination therapies. Multiple clinical trials are investigating the JAK inhibitor ruxolitinib for the treatment of T-ALL in the presence of JAK mutations 12 . Here, we show that ruxolitinib treatment is effective ex vivo in T-ALL cells with elevated JAK kinase activity.…”

“…Recurrent activating mutations detected in kinase-coding genes or kinase regulators involve the PI3K-AKT axis ( AKT1 , PIK3CD , and PIK3R1) , the JAK-STAT (IL7R, JAK1 , and JAK3 which is mutated in about 16% of T-ALL cases 6 ), or the Ras signaling pathways (PTPN11, NF1, N-RAS , and K-RAS ), while in some early T cell precursor (ETP)-ALL cases, Fms-like tyrosine kinase ( FLT3 ) mutations and/or overexpression are found 7 . Additionally, other potentially druggable kinases reported for T-ALL include the JAK-family member tyrosine kinase 2 (TYK2) which can be activated either by rare gain-of-function mutations or IL-10 signaling 8 , 9 , the cell cycle regulators Polo-like kinases (PLKs) and Aurora kinases (AURKs) 10 , 11 , and the PIM1 kinase which can be upregulated by active IL-7 signaling, upon glucocorticoid-induced IL7RA expression, or in the presence of IL-7R pathway mutations 12 , 13 .…”

Integrin signaling is critical for myeloid-mediated support of T-cell acute lymphoblastic leukemia

“…T-ALL is associated with infiltration of leukemic blasts into multiple organs, including the spleen, bone marrow (BM), lymph nodes (LN), liver, and central nervous system (2). Although current intensified chemotherapy regimens have significantly improved prognoses, with 5-year survival rates for pediatric T-ALL exceeding 90% (3,4), these therapies are toxic and are associated with long-term morbidities, such as neurological toxicity, cognitive impairment, and metabolic disorders (5,6). Moreover, the survival rate for relapsed patients is less than 25% (7)(8)(9).…”