Nucleophosmin mutations confer an independent favorable prognostic impact in 869 pediatric patients with acute myeloid leukemia

Abstract

Studies on the clinical significance of Nucleophosmin (NPM1) mutations in pediatric AML in a large cohort are lacking. Moreover, the prognosis of patients with co-occurring NPM1 and FLT3/ITD mutations is controversial. Here, we analyzed the impact of NPM1 mutations on prognoses of 869 pediatric AML patients from the TAGET dataset. The frequency of NPM1 mutations was 7.6%. NPM1 mutations were significantly associated with older age (P < 0.001), normal cytogenetics (P < 0.001), FLT3/ITD mutations (P < 0.001), and high complete remission induction rates (P < 0.05). Overall, NPM1-mutated patients had a significantly better 5-year EFS (P = 0.001) and OS (P = 0.016) compared to NPM1 wild-type patients, and this favorable impact was maintained even in the presence of FLT3/ITD mutations. Stem cell transplantation had no significant effect on the survival of patients with both NPM1 and FLT3/ITD mutations. Multivariate analysis revealed that NPM1 mutations were independent predictors of better outcome in terms of EFS (P = 0.004) and OS (P = 0.012). Our findings showed that NPM1 mutations confer an independent favorable prognostic impact in pediatric AML despite of FLT3/ITD mutations. In addition, pediatric AML patients with both NPM1 and FLT3/ITD mutations appear to have favorable prognoses and may not need hematopoietic stem cell transplantations.

The Yin and Yang-Like Clinical Implications of the CDKN2A/ARF/CDKN2B Gene Cluster in Acute Lymphoblastic Leukemia

“…Frequent codeletion of CDKN2A/B and IKZF1 (in addition to RB1 deletion and JAK/STAT pathway mutations) has also been found in Ph-like patients, a new genetic subgroup recently identified by gene expression profiling (GEP) [ 110 ] and initially including the Ph − group, suggesting that the worse outcome of this codeletion in Ph − patients could be due to the negative impact of these deletions on Ph-like patients. Consistent with this, we have recently shown that CDKN2A/B deletions could also be a marker of poor prognosis in Ph-like patients ( Table 2 ) [ 68 ].…”

“…The prognostic value of CDKN2A/B deletions is less clear in the case of Ph − BCP-ALL, probably because the genetic background of Ph − is much more heterogeneous than that of Ph + . On one hand, the UK group on ALL study suggests that CDKN2A/B losses have no impact on outcome [ 58 ], while on the other hand, analysis of smaller series of Ph − patients suggests that CDKN2A/B deletions could be a marker of poor outcome, especially concomitantly with IKZF1 [ 63 , 68 , 80 ] or RB1 deletions [ 44 ], as has been shown in pediatric cohorts [ 109 ]. Frequent codeletion of CDKN2A/B and IKZF1 (in addition to RB1 deletion and JAK/STAT pathway mutations) has also been found in Ph-like patients, a new genetic subgroup recently identified by gene expression profiling (GEP) [ 110 ] and initially including the Ph − group, suggesting that the worse outcome of this codeletion in Ph − patients could be due to the negative impact of these deletions on Ph-like patients.…”

JAK3 Is Expressed in the Nucleus of Malignant T Cells in Cutaneous T Cell Lymphoma (CTCL)

“…Moreover, environmental factors such as Staphylococcus aureus can fuel disease activity through an enhanced JAK/STAT activation, cytokine receptor expression, and proliferation of malignant T cells in situ in patients with severe CTCL. This suggest that a series of different events and factors may converge to trigger deregulated JAK/STAT signaling in malignant T cells highlighting the key role of JAK3 and downstream effectors in carcinogenesis in CTCL and other T cell malignancies [ 26 , 27 , 28 ]. Conventionally, Janus kinases are considered to be members of the class of receptor-associated tyrosine kinases (reviewed in [ 29 ]).…”

<p>Genetic Characterization and Risk Stratification of Acute Myeloid Leukemia</p>

“…The European LeukemiaNet (ELN) scheme proposes that NPM1 mutations with FLT3-ITD allele ratio (AR) <0.5 (low AR) has a favorable prognosis, and allogeneic hematopoietic stem-cell transplant (HSCT) in the first complete remission (CR1) period is not actively recommended. [22][23][24] Then in adults, CN-AML with isolated NPM1 mutations (ie the NPM1+FLT3-subgroup) exhibits a good response to chemotherapy, relapse-free survival (RFS), and improved OS. This favorable effect is however lost in the presence of an FLT3-ITD.…”