1144 POSTER Using Single-cell Network Profiling (SCNP) Signatures to Predict Response to Induction Therapy and Relapse Risk in Pediatric Patients With Acute Myeloid Leukemia (AML)

Cesano, Alessandra; Westfall, Matt; Rosen, D.; Louie, Brent; Meshinchi, Soheil; Alonzo, Todd A.; Arceci, Robert J.; Ravindranath, Y.; Dahl, GV; Lacayo, Norman J.

doi:10.1016/s0959-8049(11)70787-0

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“…Non-apoptotic leukemic cells were identified as leukemic cells negative for cPARP, an activated caspase target. Previous data demonstrated that SCNP signaling responses are robust in non-apoptotic cPARP negative cells but not in apoptotic cPARP positive cells [43], and that AML samples with less than 25% cPARP negative leukemic cells are generally not analyzable for signaling responses [44]. Thus, our current analyses include a “sample quality” cutoff of at least 25% cPARP negative leukemic cells and a measurement of SCNP signaling responses limited (by gating) to cPARP negative leukemic cells to control for sample quality differences among individual AML samples.…”

Section: Methodsmentioning

confidence: 98%

Functional Pathway Analysis Using SCNP of FLT3 Receptor Pathway Deregulation in AML Provides Prognostic Information Independent from Mutational Status

et al. 2013

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FMS-like tyrosine kinase 3 receptor (FLT3) internal tandem duplication (ITD) mutations result in constitutive activation of this receptor and have been shown to increase the risk of relapse in patients with acute myeloid leukemia (AML); however, substantial heterogeneity in clinical outcomes still exists within both the ITD mutated and unmutated AML subgroups, suggesting alternative mechanisms of disease relapse not accounted by FLT3 mutational status. Single cell network profiling (SCNP) is a multiparametric flow cytometry based assay that simultaneously measures, in a quantitative fashion and at the single cell level, both extracellular surface marker levels and changes in intracellular signaling proteins in response to extracellular modulators. We previously reported an initial characterization of FLT3 ITD-mediated signaling using SCNP. Herein SCNP was applied sequentially to two separate cohorts of samples collected from elderly AML patients at diagnosis. In the first (training) study, AML samples carrying unmutated, wild-type FLT3 (FLT3 WT) displayed a wide range of induced signaling, with a fraction having signaling profiles comparable to FLT3 ITD AML samples. Conversely, the FLT3 ITD AML samples displayed more homogeneous induced signaling, with the exception of patients with low (<40%) mutational load, which had profiles comparable to FLT3 WT AML samples. This observation was then confirmed in an independent (verification) cohort. Data from the second cohort were also used to assess the association between SCNP data and disease-free survival (DFS) in the context of FLT3 and nucleophosmin (NPM1) mutational status among patients who achieved complete remission (CR) to induction chemotherapy. The combination of SCNP read outs together with FLT3 and NPM1 molecular status improved the DFS prediction accuracy of the latter. Taken together, these results emphasize the value of comprehensive functional assessment of biologically relevant signaling pathways in AML as a basis for the development of highly predictive tests for guidance of post-remission therapy.

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Section: Methodsmentioning

confidence: 98%