Cooperation of Gene Mutations Including Class I, Class II and Tumor Suppressor Genes In Childhood Acute Myeloid Leukemia and Their Impacts on Survivals

The cooperation of gene mutations, especially their impacts on survivals of childhood acute myeloid leukemia (AML) has not been well known.

Our aims were (1) to study the frequency of each gene mutation in childhood AML, (2) to study the impact of each gene mutation on the treatment outcome, and (3) to examine the cooperativity of gene mutations.

From Feb. 1996 to Jan. 2010, bone marrow samples at diagnosis from 198 children with AML at Chang Gung Children's Hospital, Taoyuan and Mackay Memorial Hospital, Taipei, were analyzed for gene mutations including FLT3-ITD, FLT3-TKD (D835), c-KIT, cFMS, JAK 2V617F, NRAS, KRAS, PTPN11 (Class I mutations), RUNX1, CEBPα, NPM1 (Class II mutations), WT1 and P53 (tumor suppressor genes). The subtypes included: t(8;21) 19.9%, inv(16) 8.9%, t(15;17) 8.4%, t(9;11) 5.2%, t(10;11) 2.6%, trisomy 21 4.2%, intermediate-risk group 40.3% (including 13 patients with other MLL translocations), and poor-risk group 11.0% (including 7 patients with complex chromosomal abnormalities and 4 patients with MLL-PTD).

FLT3-ITD occurred in 15.0% of patients, FLT3-TKD 7.2%, c-KIT 11.5%, c-FMS 2.9%, JAK2V617F 3.3%, NRAS 9.1%, KRAS 7.7%, PTPN11 3.3%, RUNX1 2.7%, CEBPα 7.9%, NPM1 4.1%, WT1 3.9% and P53 1.7%. Taken together, 52.5% of patients had Class I gene mutations, 13.1% had Class II gene mutations, and 5.1% had WT1 or P53 mutations. In all, 59.1% of patients had Class I, Class II or tumor suppressor gene mutations. Only one patient (0.5 %) had gene mutations involving all Class I, Class II and tumor suppressor genes. Ninety-eight patients, who were treated with Taiwan Pediatric Oncology Group (TPOG) APL protocols (for acute promyelocytic leukemia) and TPOG 97A protocol (for other AML) (Liang et al, Leukemia 2006), were analyzed for survivals. In patients with t(8;21), the 5-year event-free survival (EFS) was 66±12%; 71±17% for patients with c-KIT mutations and 50±35% for the 2 patients with JAK2V617F. In patients with inv(16), the EFS of 70±15% seemed to be compromised (60±22%) for those with c-KIT mutations. In patients with t(15;17), the EFS of 78±11% was not compromised by FLT3-ITD or FLT3-TKD mutations. In patients with t(9;11), the EFS of 64% seemed to be compromised (50±35%) in the 2 patients with FLT3-TKD mutations. In 3 patients with t(10;11), no gene mutations were found. In trisomy 21, the EFS of 75±22% seemed to be compromised (50±35%) in the 2 patients with CEBPα mutations. Of the 5 patients with complex chromosomal abnormalities, the only one patient carrying RUNX1 survived. Of the 3 patients with MLL-PTD having an EFS of 33±27%, one each patient with c-FMS or WT1 mutation died. The only one patient who had all Class I, Class II and tumor suppressor gene mutations (FLT3-TKD+ CEBPα+ WT1) died in induction therapy. Two of the other 4 patients who had 3 mutations acrossing 2 classes had EFS of 6 and 10 months, respectively.

Our study on a large cohort of pediatric AML patients revealed that 59.1% patients had at least one gene mutation. That 3 of 5 patients who had 3 gene mutations soon failed suggested that gene mutations, especially in 3 combinations, might compromise the survival. Further study on more patients is warranted to explore more of the prognostic significance of cooperating gene mutations in pediatric AML.

(Supported by grants MMH-E-98009, NSC 96–2314-B-195-006-MY3, NHRI-EX-96-9434SI and DOH99-TD-C-111-006.)

No relevant conflicts of interest to declare.