Disease Usual phenotype
acute leukemia precursor
chronic leukemia differentiated
lymphoma
myeloma
Total WBC Blast Pro Myel Meta Band PMN
> 60
leukemoid 0 0 0 2 13 82
reaction
acute 80 0 0 0 3 10
leukemia
chronic 2 8 15 18 20 37
myeloid
leukemia
Chronic myeloid leukemia
Chronic phase
increased pool of clonal precursors
committed to become myeloid cells
most of the clonal precursors
differentiate into mature cells
Conversion of proto-oncogene
to oncogene
• Possible mechanisms
– Unaltered gene product (e.g., myc in Burkitt’s)
– Altered gene product
» usually a fusion protein (e.g., bcr-abl in CML)
CML - chronic phase
• weakness, weight loss, purpura
• thrombocytosis
• anemia - normal MCV
• splenomegaly
• priapism
• median duration 3-4 yrs
Leukemias - evidence of
damage to DNA
• majority have visible chromosomal abnormality
• tumor-specific chromosomal translocations,
e.g.,
– t(15;17) acute promyelocytic leukemia
– t(9;22) chronic myeloid leukemia
– t(8;14) Burkitt’s lymphoma/leukemia
CML - chronic phase
• WBC increased
• Entire granulocytic spectrum on blood film
• Marrow hyperplasia
– expanded myeloid series
– eo and basophil precursors
– megakaryocytes
• Low neutrophil alkaline phosphatase
• Ph chromosome [t(9;22)] present
Ph chromosome: t(9;22)
• reciprocal translocation between long arms
of chromosomes 9 and 22
• Ph-negative CML: 9;22 translocation present
but not visible
• ABL sequences from 9 translocated into
BCR gene on 22 FUSION GENE
Introduction of BCR-ABL gene
into mice
• trans-genic model
• bcr-abl product expressed
• animals develop CML and/or ALL
molecular tyrosine kinase
weight activity
normal ABL on 145,000 weak
chromosome 9
fusion gene on 210,000 strong
chromosome 22
bcr-abl protein differs from abl protein
• cytoplasmic location
• transforms cells in vitro
• increased tyrosine kinase activity
• new substrates and binding proteins
• ras is activated
• bcr component contributes to transforming activity
Chronic myeloid leukemia
Ph chromosome present in precursors of:
• granulocytes
• monocytes/macrophages
• basophils
• eosinophils
• erythrocytes
• platelets
• some B lymphocytes
Treatment of CML - chronic phase
• busulfan
• hydroxyurea
• interferon- 10-20% lose Ph chromosome
• survival better with hydroxyurea or interferon
• Imatinib (STI571) - targets ABL, potent, little toxicity
• allogeneic transplantation potentially curative
CML - allogeneic transplantation
• may result in cure
• 10-25% transplant-related mortality
• age, donor limitations
• mechanisms of cure
– high dose chemoradiotherapy
– graft vs leukemia
GvHD v GvL
Graft versus Host
Disease
Normal cells
Donor T lymphocytes Graft versus
Leukemia effect
Leukemic cells
Frequency of GVHD and relapse after alloBMT
unrelated
donor
HLA-identical
Increasing sibling donor
Increasing
GVHD Relapse
T-cell depleted
syngeneic
CML in blastic transformation
• unstable disease
• weight loss, fever, sweats, bone pain
• worsening
splenomegaly
anemia
platelet counts
blast and promyelocyte counts
basophilia and eosinophilia
• resistance to therapy
• ‘blastic crisis’ develops in most
• death in weeks or months
CML in blastic transformation
• Blasts of variable phenotype
myeloid
megakaryocytic
erythroid
lymphoid (early B cell)
• ‘Clonal evolution’
Ph chromosome with additional mutations
(e.g., double Ph, trisomy 8, p53 alteration)
Ph-positive ALL
• 20-30% of adult ALL
• poor prognosis
• some have same fusion gene as in CML
• different fusion gene in others
– breakpoints more 5’ in BCR
– gene product 190,000 daltons
– even stronger tyrosine kinase activity
Oncogene Activation
Trans- Proposed mechanism
location Disease
t(8;14) some B-cell expression of
lymphomas, ALL transcription factor
(myc)
t(9;22) CML, chimeric signalling
some ALL molecule
(bcr-abl)
t(15;17) acute chimeric
promyelocytic transcription factor
leukemia (pml-rar
CML as a model of human malignancy
• origin in a stem cell
• tumor cell phenotype is differentiated (variably)
• clonal
• proliferative advantage
• genetic instability
– tendency to become less differentiated
Chronic myeloproliferative disorders
• chronic myeloid leukemia
• myelofibrosis with myeloid metaplasia
• polycythemia vera
• essential thrombocythemia
CML, myeloid metaplasia, P vera,
essential thrombocythemia
• clonal
• arising in stem cells, with involvement of
several cell lines
• leukocytosis
• thrombocytosis and platelet dysfunction
• splenomegaly
• tendency to convert to acute leukemia
Myelofibrosis with Myeloid Metaplasia
• WBC increased, normal, or decreased
• Differential similar to CML
• anisopoikilocytosis
• tear-drop RBC’s
• nucleated RBC’s
• fibrosis of marrow
– fibroblasts not part of clone
