FLT3 Mutations in Early T-Cell Precursor ALL Characterize a Stem Cell Like Leukemia and Imply the Clinical Use of Tyrosine Kinase Inhibitors

Abstract

Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) has been identified as high-risk subgroup of acute T-lymphoblastic leukemia (T-ALL) with a high rate of FLT3-mutations in adults. To unravel the underlying pathomechanisms and the clinical course we assessed molecular alterations and clinical characteristics in a large cohort of ETP-ALL (n = 68) in comparison to non-ETP T-ALL adult patients. Interestingly, we found a high rate of FLT3-mutations in ETP-ALL samples (n = 24, 35%). Furthermore, FLT3 mutated ETP-ALL was characterized by a specific immunophenotype (CD2+/CD5-/CD13+/CD33-), a distinct gene expression pattern (aberrant expression of IGFBP7, WT1, GATA3) and mutational status (absence of NOTCH1 mutations and a low frequency, 21%, of clonal TCR rearrangements). The observed low GATA3 expression and high WT1 expression in combination with lack of NOTCH1 mutations and a low rate of TCR rearrangements point to a leukemic transformation at the pluripotent prothymocyte stage in FLT3 mutated ETP-ALL. The clinical outcome in ETP-ALL patients was poor, but encouraging in those patients with allogeneic stem cell transplantation (3-year OS: 74%). To further explore the efficacy of targeted therapies, we demonstrate that T-ALL cell lines transfected with FLT3 expression constructs were particularly sensitive to tyrosine kinase inhibitors. In conclusion, FLT3 mutated ETP-ALL defines a molecular distinct stem cell like leukemic subtype. These data warrant clinical studies with the implementation of FLT3 inhibitors in addition to early allogeneic stem cell transplantation for this high risk subgroup.

The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia

“…by guest www.bloodjournal.org From early T-cell differentiation, with retention of some myeloid and stem cell characteristics at both the immunophenotypic and genetic level. [128][129][130][131] By definition, blasts in ETP ALL express CD7 but lack CD1a and CD8, and are positive for 1 or more of the myeloid/stem cell markers CD34, CD117, HLADR, CD13, CD33, CD11b, or CD65. 128 They typically also express CD2 and cytoplasmic CD3 and may express CD4, but these are not part of the definition.…”

Stat5 is critical for the development and maintenance of myeloproliferative neoplasm initiated by Nf1 deficiency

“…[62][63][64][65] Like acute myeloid leukemia, most ETP ALL harbor mutations that activate RAS and RAS pathway components. 63,65,66 JAK1 and JAK3 are also commonly mutated in ETP ALL. 65,66 Recently, activated STAT5 (phospho-STAT5) levels were found to be elevated in all ETP-ALL cases tested.…”

Poor Response to Standard Chemotherapy in Early T-precursor (ETP)-ALL: A Subtype of T-ALL Associated with Unfavourable Outcome: A Brief Report

“…Neumann et al [10] in another study analysed 68 patients of ETP-ALL out of which data on clinical follow-up was available in 52 patients. Forty-five patients were treated according to a GMALL-like protocol, three patients to an AML-like protocol.…”

“…Even among ETP-ALL patients, patients with a FLT3 mutation show a distinct immunophenotype with positivity for CD117, CD34, CD13 and CD2. In contrast, ETP-ALL patients with a FLT3 wild-type status have more often positivity for CD5 and CD33 [9,10].…”