Progenitor cell involvement is predictive of response to induction chemotherapy in paediatric acute myeloid leukaemia

Abstract

Summary. In acute myeloid leukaemia (AML), involvement of early progenitor cells may predict poor response to induction chemotherapy. We evaluated the involvement of early progenitor cells in two AML subtypes with a favourable prognosis [t(8;21) and t(15;17)], and a subtype with poor prognosis (monosomy 7). CD34 + CD33 ) cells were isolated by fluorescence-activated cell sorting, grown in liquid medium followed by culture in semi-solid medium, and the colonies that were formed were analysed for the identifiable genetic markers. Two of 136 colonies from six t(8;21) AML patients expressed the AML1-ETO transcript, and all six patients achieved remission after induction. None of 192 colonies from five t(15;17) AML patients expressed the RARa-PML transcript and all achieved remission. In contrast, in three of 10 cases of monosomy 7 AML, colonies were positive for monosomy 7, and all three patients failed to enter remission. However, five of six evaluable patients with colonies negative for monosomy 7 entered remission. These data support the hypothesis that leukaemic involvement of early progenitor cells affects the response to induction chemotherapy.Keywords: progenitor cells, acute myeloid leukaemia, chemotherapy response, monosomy 7, prognosis.We hypothesized that leukaemic involvement of early progenitor cells may predict for poor response to induction chemotherapy in acute myeloid leukaemia (AML). Therefore, we evaluated the leukaemic involvement of early precursors in two AML subtypes with a favourable prognosis, t(8;21) (Woods et al, 1985;Lemons et al, 1995) and t(15;17) (Turhan et al, 1995;Chang et al, 2000); and a subtype with a poor prognosis, monosomy 7 (LunaFineman et al, 1995). Previous studies have shown variable stem cell involvement in AML, with aberrant cells present in the CD34 + Lin ) (i.e. CD34 + CD33 ) CD38 ) ) compartment of the leukaemic specimens (Mehrotra et al, 1995), but CD34 + CD33 ) cells cultured in semi-solid conditions generated cytogenetically normal progenitors (Raymakers et al, 1995). We used a liquid culture system that supports the proliferation of more immature precursors with greater proliferative potential. From a primitive CD34 + CD33 ) subpopulation, CD34 + CD33 ) cells were isolated by fluorescence-activated cell sorting (FACS) and grown in liquid medium for 7 d prior to plating in semi-solid medium for 12-14 d. These culture times were chosen based on previous experience in this laboratory with isolating immature precursors, which were able to proliferate in vitro. Granulocyte macrophage colony-forming unit (CFU-GM) colonies were collected from these cultures and analysed for molecular markers associated with the malignant clone using fluorescence in situ hybridization (FISH) to detect the presence of monosomy 7, and reverse transcription polymerase chain reaction (RT-PCR) to detect leukaemia-specific chimaeric mRNA produced by t(8;21) or t(15;17) gene expression. The presence of the chromosomal aberration was evaluated for a correlation with response to induction chemothe...

FLT3 internal tandem duplication in CD34+/CD33- precursors predicts poor outcome in acute myeloid leukemia

“…For example, APL, a disease that is limited to a mature precursor population, has excellent clinical outcome. 3,26,27 Moreover, studies in monosomy 7 (Ϫ7) AML demonstrate that response to induction chemotherapy correlates with extent of early progenitor cell involvement, with patients demonstrating the cytogenetic abnormality in less-mature CD34 ϩ /CD33 Ϫ hematopoietic progenitors having worse response to induction therapy than patients in which Ϫ7 is limited to a more differentiated population. 3 Our data further support this concept, suggesting that FLT3/ITD detection is heterogeneous in CD34 ϩ /CD33 Ϫ myeloid progenitors and that disease involvement of this precursor population may correlate with poor clinical outcome.…”

“…1,2,24 Alternatively, disease may evolve from a committed myeloid progenitor, as is thought to be the case with acute promyelocytic leukemia (APL). 3,25,26 Ultimately, the maturational stage at which frank leukemic transformation occurs may dictate clinical response. For example, APL, a disease that is limited to a mature precursor population, has excellent clinical outcome.…”

“…2 Evidence that disease involvement of CD34 ϩ /CD33 Ϫ progenitors might correlate with response to chemotherapy came from the observation that patients with monosomy 7 AML carrying the cytogenetic abnormality in immature CD34 ϩ /CD33 Ϫ progenitor cells had higher rates of induction failure than patients lacking the mutation in this early progenitor population. 3 In the present study we tested whether the clinical heterogeneity seen in AML might reflect differences in disease involvement of an immature CD34 ϩ /CD33 Ϫ progenitor population and whether such heterogeneity has therapeutic implications. Specifically, are patients with high-risk disease more likely to have requisite mutations detected in less-mature CD34 ϩ /CD33 Ϫ hematopoietic progenitors than patients with favorable outcome?…”

Correlation of CD33 expression level with disease characteristics and response to gemtuzumab ozogamicin containing chemotherapy in childhood AML

“…Previous in vitro work suggested that the maturational stage at which leukemic transformation occurs may dictate clinical response, with more favorable outcomes seen when disease is derived from a more committed myeloid progenitor. [22][23][24][25] If this is the case, then those patients with CD33 low/absent blast expression may be more sensitive to conventional chemotherapy and potentially GO, assuming that CD33 expression, if present, is sufficient for GO targeting.…”

Therapeutic Implications of Leukemia Stem Cell Development

“…-cells harboring the monosomy 7 abnormality did not respond well to induction therapy (8). Future detailed studies should determine the extent of committed progenitor cells as the cell of origin in human AML, and if the cell of origin influences outcome.…”