Integrated clinical genotype-phenotype characteristics of early T-cell precursor acute lymphoblastic leukemia.

BACKGROUND: Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a distinct subtype of T-ALL with a unique immunophenotype and high treatment failure rate. The molecular genetic abnormalities and their prognostic impact in ETP-ALL patients are poorly understood. METHODS: The authors performed systematic analyses of the clinicopathologic features with an emphasis on molecular genetic aspects of 32 patients with ETP-ALL. RESULTS: The median age was 43 years (range, 16-71). The blasts were positive for cytoplasmic CD3 and CD7 and negative for CD1a and CD8. Other markers expressed included CD34 (88%), CD33 (72%), CD117 (68%), CD13 (58%), CD5 (partial, 56%), CD2 (38%), CD10 (25%), CD56 (partial, 19%), and CD4 (6%). Cytogenetic analyses revealed a diploid karyotype in 10 patients, simple (1-2) abnormalities in 10 patients, and complex karyotype in 10 patients. Next-generation sequencing for 21 patients demonstrated that all had gene mutations (median, four mutations per patient). The most frequently mutated genes were WT1 (38%), NOTCH1 (29%), NRAS (29%), PHF6 (25%), TP53 (24%), ASXL1 (19%), FLT3 (19%), and IKZF1 (19%). All patients except one received multi-agent chemotherapy, and 22 patients underwent allogeneic stem cell transplantation. Thrombocytopenia, an abnormal karyotype, and TP53 mutation were associated with markedly shortened overall survival. Stem cell transplantation significantly improved overall survival. CONCLUSIONS: Patients with ETP-ALL often have high mutation burden with increased genomic instability. TP53 mutation was the only molecular prognostic marker and was associated with complex karyotype and greater than or equal to five mutations. These patients may benefit from stem cell transplantation, and recurrent gene mutations may be novel therapeutic markers.

Downregulation of FAPP2 gene induces cell autophagy and inhibits PI3K/AKT/mTOR pathway in T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy. Most patients with T-ALL are treated with high-dose multi-agent chemotherapy due to limited targeted therapeutic options. To further investigate its pathogenesis and establish new therapeutic targets, we studied the role of FAPP2, a Golgi protein, that is, highly expressed in T-ALL, in the growth and function of T-ALL. We found that T-ALL cells underwent reduced cell proliferation and sub-G1 accumulation after knocking down of FAPP2 gene using shRNA systems. Instead, FAPP2 downregulation promoted cell autophagy. The level of autophagy markers, LC3Ⅱ/Ⅰ, Beclin1, and ATG5, was markedly increased, whereas that of P62 decreased after FAPP2 knocking down in T-ALL cells. FAPP2 knocking down led to the accumulation of LC3 in the cytoplasm of T-ALL cells as shown by fluorescence microscopy. In addition, the level of PI(4)P and PI(3,4,5)P decreased and phosphorylation of P-AKT and P-mTOR were downregulated in FAPP2 knock-down cells. In summary, our results show that decreased expression of FAPP2 inhibited cell proliferation, resulted in the sub-G1 phase accumulation of T-ALL cells, and enhanced autophagy of T-ALL cells, likely mediated by PI(4)P, PI(3,4,5)P, and PI3K/AKT/mTOR pathway. Our results provide a new insight into the pathogenesis and development of potential targeted therapy of T-ALL.

Integrated Clinical Genotype-phenotype Characteristics of STAT3-mutated Myeloid Neoplasms.

PURPOSE: STAT3 is a key transcription factor that mediates cancer progression through phosphorylation or gain-of-function mutations. STAT3 activation in myeloid neoplasms (MNs) is primarily mediated through phosphorylation. STAT3 mutation has only rarely been reported in MNs. EXPERIMENTAL DESIGN: We assessed the clinicopathologic and molecular genetic features of 32 STAT3-mutated MNs. RESULTS: The frequency of STAT3 mutation in MNs was <0.5%. Twenty (62.5%) cases were classified as acute myeloid leukemia (AML), 7 (21.9%) as myelodysplastic syndrome (MDS), 5 (15.6%) as chronic myelomonocytic leukemia (CMML), but none as myeloproliferative neoplasms (MPN). STAT3 mutations occurred at initial diagnosis in 22 (88%) cases, or at relapse or upon leukemic transformation. Clonal hierarchy analysis revealed that STAT3 mutations represented the dominant clone in 30% of AML cases, but were subclonal in MDS and CMML. Most were missense mutations located at the SH2 domain, Y640F being the most common. STAT3 mutation was accompanied by co-existing mutations in all cases, most frequently SRSF2, TET2, ASXL1, and SETBP1. STAT3 mutations were usually associated with morphologic dysplasia, increased blasts, and monosomy 7/del7q. With a median follow-up of 24.5 months, 21 patients died, 6 had persistent disease, and 5 achieved complete remission after stem cell transplantation. CONCLUSIONS: STAT3 mutation is present in various MNs, but not in MPN. It is often an early event or occurs upon leukemic transformation, suggesting an important role in the pathogenesis and progression of MNs by activating JAK-STAT pathway. It may help identify a subset of patients with MNs who may benefit from targeted therapy.

B-Lymphoblastic Leukemia With Aberrant CD5 Expression.

OBJECTIVES: B-acute lymphoblastic leukemia (B-ALL) is a neoplasm of precursor lymphoid cells committed to the B-lineage. Expression of CD5 is rare in B-ALL. METHODS: We studied the clinicopathologic, immunophenotypic, and molecular genetic features of 10 cases of B-ALL with aberrant CD5 expression, and compared with CD5-B-ALL. RESULTS: B-ALL with aberrant CD5 expression is rare and predominantly affects men. Patients with CD5+ B-ALL had shorter median overall survival (21 vs 45 months, P = .0003). Expression of CD5 imposed a challenge in the differential diagnoses between B-ALL and other CD5+ B-cell lymphomas with blastic morphology. Dim CD20 and CD45, lack of surface immunoglobulin, expression of CD34 and TdT, negative immunostain for cyclin D1, and absence of t(11;14)(q13;q32) support a diagnosis of B-ALL. CONCLUSIONS: CD5 expression is rare in B-ALL and associated with poor clinical outcome. CD5+ B-ALL represents a distinct entity that needs to be considered in the differential diagnoses of CD5+ B-cell lymphoproliferative disorders.