Phenotypic and molecular heterogeneity in Philadelphia chromosome- positive acute leukemia

Abstract

Philadelphia chromosome-positive (Ph1) acute leukemia is a heterogeneous subset of acute leukemia with a poor prognosis. We studied five patients to determine the potential for phenotypic and molecular heterogeneity. Cellular characterization studies included light myeloperoxidase (L-MPO), terminal deoxynucleotidyl transferase (TdT), ultrastructural MPO (U-MPO), and immunophenotyping by flow cytometry using T11, T3, T4, T8, Leu 1, B1, Leu 12, HLA-DR (la), CALLA (J5), OKM1, My4, My7, My8, My9, and My10. DNA was analyzed for rearrangements of the breakpoint cluster region (bcr), immunoglobulin heavy chain, joining region (JH), immunoglobulin kappa light chain constant region (C kappa), and T cell receptor (TcR beta). RNA dot blots were hybridized by using molecular probes for MPO and TdT. We found that four of five cases were acute mixed-lineage leukemia (AMLL). One patient had acute unclassifiable leukemia. Of the four patients classified as having AMLL, three showed myeloid and lymphoid features, with one patient showing myeloid, T cell, and B cell features. The last case showed T cell and B cell features only. In one patient MPO/RNA was positive in spite of insufficient L-MPO or U-MPO to diagnose acute myelogenous leukemia (AML), thereby suggesting significant MPO gene expression before the production of sufficient MPO protein to meet the French-American-British criteria for AML. Three of the five patients showed rearrangement of bcr (cases 1, 2, and 5). Studies of these five patients support the concepts of molecular and phenotypic heterogeneity in Ph1 acute leukemia, demonstrate a high incidence of AMLL in this subset of acute leukemia, and support the use of lineage-associated molecular probes to define lineage at an earlier stage than previously possible.

The P190, P210, and P230 Forms of the BCR/ABL Oncogene Induce a Similar Chronic Myeloid Leukemia–like Syndrome in Mice but Have Different Lymphoid Leukemogenic Activity

“…In Ph-positive ALL, about half of adult patients have traditional BCR intron 13 or 14 breakpoints on chromosome 22 generating the P210 form of BCR/ABL. Some of these patients have persistence of the Ph chromosome in remission and carry the Ph chromosome in myeloid cells and myeloid colonies grown in vitro, suggesting they represent cases of CML presenting in blast crisis after an unrecognized chronic phase (6)(7)(8)49). In contrast, the majority of ALL patients with the BCR intron 1 breakpoint characteristic of P190 BCR/ABL do not exhibit the additional cytogenetic abnormalities typical of CML blast crisis, lack the Ph chromosome in myeloid cells, and become Ph-negative during clinical remissions, suggesting they represent transformation of a cell type that is more limited in its differentiation potential (50).…”

“…Different Leukemogenic Activity of P190, P210, and P230 BCR/ABL In humans, there is evidence that the three different forms of BCR/ABL are associated with distinct forms of leukemia (for reviews, see references 4 and 5). The P210 form of BCR/ABL is found in hematopoietic cells of patients with chronic myeloid leukemia (CML) in stable phase, and in acute lymphoid and myeloid leukemias (6)(7)(8), although some patients with acute leukemia and P210 are likely to be cases of CML diagnosed in blast crisis. In contrast, the P190 form of BCR/ABL is commonly found in Ph-positive acute B lymphoid leukemia (ALL [9]) and occasionally in acute myeloid leukemia (10), but is rarely if ever observed in CML (11)(12)(13).…”

Inzidenz, klinische Merkmale und prognostische Bedeutung immunologischer Subtypen der akuten lymphoblastischen Leukämie (ALL) im Kindesalter: Erfahrungen der Therapiestudien ALL-BFM 83 und 86

“…Die Rezidivkaskade brach für Kinder mit common ALL erst nach etwa 4 1 / 2 Jahren ab und das EFS liegt mit 67frJo um mehr als lOfrJo höher als für Patienten mit prä-T IT-ALL (56frJo), bei denen die Rezidive überwiegend innerhalb der ersten 1 1 / 2 Jahre auftraten und ein Plateau der Life-Table Kurve bereits nach etwa 2 1 / 2 Jahren erreicht wurde. Alle Rezidive bei Kindern mit B-ALL ereigneten sich im ersten 1/ 2 Jahr nach Diagnose und die Wahrscheinlichkeit für das EFS beträgt 0,27. Da nur bei etwa 50frJo der Patienten mit B-ALL in der Studie ALL-BFM 83 eine immunologische Typisierung durchgeführt werden konnte, kann dieses ungünstige Therapieergebnis nicht als repräsentativ für die Gesamtgruppe der Kinder mit B-ALL angesehen werden (15).…”

“…Die in der ALL-BFM Studie 86 beobachtete niedrige Inzidenz der Koexpression myeloischer Antigene (35 von 570 Patienten, 6,1 frJo) entspricht früheren Auswertungen der BFM Studien (37) und Berichten anderer Autoren (1,3, 14,30,65). Verschiedene Studien,sowohl bei Kindern (44,45,49) als auch bei Erwachsenen (27,61) mit ALL, haben jedoch einen deutlich höheren Prozentsatz an My-positiver ALL ergeben. Die in diesen Studien nicht einheitlich verwendete Definition der My-positiven ALL, z. T. fehlende Linienspezifität der analysierten myeloischen Antigene (z.…”