The Clinical Role of Micrornas (miRs) in Cytogenetically Normal (CN) Acute Myeloid Leukemia (AML): miR-155 Upregulation Independently Identifies High-Risk Patients (Pts)

Abstract 1387 [][1] miR-155 is upregulated in aggressive subtypes of solid tumors and leukemia. In AML, higher miR-155 expression is associated with FLT3 -ITD. However, whether miR-155 upregulation impacts on clinical outcome independently from FLT3 -ITD and other prognosticators is unknown. We evaluated the prognostic impact of miR-155 in 363 CN-AML pts (153 age <60 y; 210 age ≥60 y) that were treated with cytarabine-daunorubicin-based regimens and had a median follow-up of 7.9 y (range, 2.3–12.9). miR-155 levels were measured in pretreatment marrow or blood by the NanoString nCounter assay quantifying expression of the encoding gene MIR155HG ; other molecular markers were assessed centrally. High miR-155 expressers ( miR-155 ) had higher WBC ( P <.001) and were more often FLT3 -ITD-positive (pos; P <.001), RUNX1 -mutated (mut; <.001), WT1 -mut ( P =.03), ↑ ERG ( P =.02) and ↑ BAALC ( P =.002), and less often CEBPA -mut ( P =.003), IDH2 -mut ( P =.004) and FLT3 -TKD-pos ( P =.08) than low expressers (↓ miR-155 ). ↑ miR-155 had lower CR rates ( P <.001), shorter DFS ( P =.001) and OS ( P <.001), than ↓ miR-155 . In multivariable analyses (MVA; [Table][2]), ↑ miR-155 was associated with lower CR rates ( P =.007) and shorter OS ( P <.001). Among younger pts, ↑ miR-155 had lower CR rates ( P =.03) and shorter DFS ( P <.001) and OS ( P <.001) than ↓ miR-155 . In MVA ([Table][2]), ↑ miR-155 status remained associated with worse CR rate ( P =.06), shorter DFS ( P =.003) and OS ( P =.01). Among older pts, ↑ miR-155 had lower CR rates ( P =.008) and shorter OS ( P <.001); in MVA ([Table][2]), ↑ miR-155 remained associated with worse CR ( P =.03) and shorter OS ( P =.05). In the European LeukemiaNet classification, younger ↑ miR-155 in the Favorable (Fav) Genetic Group (GG; CEBPA -mut and/or NPM1 -mut without FLT3 -ITD) had lower CR rates ( P =.03) and shorter DFS ( P =.04) and OS ( P =.02) than ↓ miR-155 . In the younger Intermediate-I (Int-I) GG pts (with wild-type CEBPA, NPM1 -mut with FLT3 -ITD, or wild-type NPM1 ), miR-155 expression did not impact independently on outcome. In older pts, ↑ miR-155 had a shorter OS both in the Fav ( P =.06) and Int-I GGs ( P =.05) than ↓ miR-155 . To gain biologic insights, w e derived an Affymetrix gene-expression signature that comprised 196 mRNAs significantly correlated with miR-155 expression. Consistent with previous mechanistic studies, Gene Ontology analysis revealed that the ↑ miR-155 -associated signature was enriched for genes involved in anti-apoptotic, proliferative and inflammatory activities (FDR<0.05). ↑ miR-155 was not significantly correlated with that of any other microRNAs (miRs) thereby supporting the unique role of miR-155 among the miRs in AML. In summary, miR-155 expression is independently associated with clinical outcome in CN-AML and may allow for better evaluation of molecular risk, especially in pts lacking FLT3 -ITD, like those in the ELN Fav GG. Moreover, given its role in deregulation of fundamental mechanisms of cell homeostasis and the emergence of miR inhibitors, miR-155 may become a novel therapeutic target. | Group | CR | DFS | OS | |:------------------------------:| ---- | ----- | -------------------------------------------------------- | ----- | | OR | P | HR | P | HR | P | | All pts | | | miR-155 expression not significantly associated with DFS | a | | | miR-155 , ↑ v ↓ | 0.46 | .007 | 1.62 | <.001 | | NPM1 , mut v wt | 2.42 | .005 | | | | BAALC , ↑ v ↓ | 0.37 | .002 | 2.16 | <.001 | | WBC, each 50 units | 0.65 | <.001 | | | | Age group, older v younger | 0.43 | .003 | 2.38 | <.001 | | FLT3 -ITD, pos v neg | | | 1.78 | <.001 | | Race, white v nonwhite | | | 1.62 | .03 | | Pts age < 60 y | | | | | | | | miR-155 , ↑ v ↓ | 0.39 | .06 | 2.13 | .003 | 1.84 | .01 | | RUNX1 , mut v wt | 0.21 | .01 | | | | | | Age, each 10 y increase | 0.45 | .004 | | | | | | WBC, each 50 units | | | | | 1.49 | <.001 | | FLT3 -ITD, pos v neg | | | 2.82 | <.001 | 1.82 | .01 | | FLT3 -TKD, pos v neg | | | 3.27 | <.001 | | | | BAALC , ↑ v ↓ | | | 2.66 | <.001 | 2.33 | <.001 | | Race, white v nonwhite | | | 2.81 | .02 | | | | CEBPA , mut v wt | | | | | 0.47 | .02 | | WT1 , mut v wt | | | | | 2.25 | .005 | | Pts age ≥ 60 y | | | miR-155 expression not significantly associated with DFS | | | | miR-155 , ↑ v ↓ | 0.46 | .03 | 1.36 | .05 | | NPM1 , mut v wt | 2.45 | .03 | | | | BAALC , ↑ v ↓ | 0.32 | .004 | 2.18 | <.001 | | WBC, each 50 units | 0.65 | .005 | | | | Age, each 10 y increase | 0.48 | .02 | | | | FLT3 -ITD, pos v neg | | | 1.56 | .006 | * ↑, high expression; ↓, low expression; CR, complete remission; DFS, disease-free survival; HR, hazard ratio; mut, mutated; neg, negative; OR, odds ratio; OS, overall survival; pos, positive; WBC, white blood count; wt, wild-type. Table. MVA in pts with primary CN-AML Odds ratios > ( (<) 1.0 mean higher (lower) risk of relapse or death (DFS) or death (OS) for the higher values of continuous variables and the 1st category listed for categorical variables. Disclosures: No relevant conflicts of interest to declare. [1]: #fn-3 [2]: #T1