Chronic Myeloid Leukemia

Slide 1 · Chronic myeloid leukemia

Molecular basis • diagnostic morphology • disease evolution

BCR::ABL → constitutive ABL kinase signaling

A pathology lecture grounded in Robbins, Cotran & Kumar

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes

Trace the t(9;22) rearrangement to constitutive BCR-ABL signaling.

Explain the characteristic peripheral blood, marrow, and splenic findings.

Select tests that establish the molecular identity of CML.

Relate clonal evolution and kinase inhibition to the disease course.

Mechanism → morphology → diagnosis → clinical outcome

Slide 3 · CML belongs to the myeloproliferative neoplasms

MPNs are clonal expansions driven by aberrant growth and survival signaling.

They commonly overproduce differentiated blood cells.

CML is distinguished by a specific BCR::ABL gene fusion.

Activated signaling

Marrow expansion

Mature cells in blood

Slide 4 · CML has a defining molecular lesion

The characteristic lesion combines sequences from BCR on chromosome 22 and ABL on chromosome 9.

The resulting fusion encodes a constitutively active tyrosine kinase.

A molecular test can therefore identify the disease, not merely support a morphologic impression.

BCR::ABL

Fusion oncogene

Slide 5 · Stem-cell origin explains multilineage potential

The initiating neoplastic cell is a pluripotent hematopoietic stem cell.

Its descendants expand especially in granulocytic and megakaryocytic compartments.

Both myeloid and lymphoid blast crises are possible after progression.

Pluripotent HSC

Myeloid potential

Lymphoid potential

Slide 6 · Proliferation increases without a maturation block

The founding BCR-ABL kinase promotes proliferation and survival.

It does not, by itself, prevent differentiation.

Consequently, chronic-phase blood contains many maturing and mature granulocytes.

CML: Expansion + maturation

Acute leukemia: Blast accumulation

Slide 7 · Growth-factor independence: The central MPN principle

Normal growth factors regulate tyrosine kinase signaling.

Oncogenic signaling allows progenitors to proliferate with reduced dependence on these controls.

In CML, the BCR-ABL fusion protein provides this abnormal signal.

Normal input

BCR-ABL bypass

Persistent proliferation

Slide 8 · The Philadelphia rearrangement involves 9 and 22

The usual cytogenetic event is reciprocal t(9;22)(q34;q11).

A derivative chromosome 22 carries the BCR::ABL fusion.

The rearrangement is conventionally called the Philadelphia chromosome.

Reciprocal t(9;22)

9

22

Der(9)

Der(22) / Ph

ABL

BCR

Schematic gene exchange — not a karyotype

Slide 9 · The two partner genes contribute distinct functions

BCR contributes a self-associating dimerization region.

ABL supplies the tyrosine kinase catalytic component.

Their fusion changes the normal control of ABL activity.

BCR: Association

ABL: Kinase

Slide 10 · BCR::ABL is the gene; BCR-ABL is its protein

BCR::ABL denotes the rearranged genetic sequence.

BCR-ABL denotes the encoded chimeric tyrosine kinase.

Distinguishing the gene from the protein clarifies diagnostic and therapeutic language.

BCR::ABL — fusion gene

BCR-ABL — fusion kinase

Slide 11 · Most cases show a visible Philadelphia translocation

More than 90% of cases have the classic reciprocal rearrangement.

Conventional chromosome analysis can demonstrate t(9;22).

A minority require molecular methods to reveal a cryptic or complex fusion.

>90%: Classic t(9;22)

Remainder: Cryptic / complex

Slide 12 · Cryptic BCR::ABL may escape routine karyotyping

The fusion can arise through cytogenetically complex or cryptic events.

Absence of a visibly recognizable Ph chromosome does not exclude BCR::ABL.

Fluorescence in situ hybridization and PCR-based tests can detect these cases.

Conventional study

Unresolved suspicion

FISH / PCR-based test

Slide 13 · CML usually produces the 210-kDa BCR-ABL protein

The typical fusion product in CML is about 210 kDa.

Its biological importance is constitutive ABL kinase activity.

Protein size is not a substitute for demonstrating the fusion genetically.

P210

BCR-ABL kinase

Slide 14 · Normal kinase activation is regulated

Ligand-dependent receptor activation ordinarily promotes dimerization.

Autophosphorylation initiates signaling through downstream substrates.

This architecture ties signaling to physiological inputs.

Growth factor

Regulated kinase

Downstream signals

Slide 15 · BCR-mediated dimerization switches ABL on

The BCR region self-associates, bringing fusion proteins together.

This permits inappropriate ABL kinase activation.

Signaling persists in the absence of ordinary growth-factor regulation.

BCR dimerization

ABL activation

Persistent kinase activity

Slide 16 · Constitutive signaling drives two main outcomes

Survival signaling allows expansion of abnormal progenitors.

Proliferative signaling increases their production of progeny.

Together these outputs support the highly cellular marrow and leukocytosis.

Active BCR-ABL

Proliferation

Survival

Slide 17 · The RAS pathway contributes to growth signals

BCR-ABL activates downstream pathways that include RAS signaling.

These pathways normally participate in growth-factor responses.

Constitutive upstream activity sustains progenitor proliferation.

BCR-ABL

RAS pathway

Cell proliferation

Slide 18 · The JAK/STAT pathway supports the neoplastic clone

BCR-ABL also activates the JAK/STAT pathway.

Its signaling contributes to prosurvival and progrowth effects.

The hallmark is inappropriate pathway activation, not an asserted unique pathway dependency.

BCR-ABL

JAK / STAT

Survival + growth

Slide 19 · Multiple signals converge on increased cell output

The kinase activates more than one downstream effector pathway.

Granulocytic and megakaryocytic progenitors respond prominently.

The net result is excess differentiated granulocytes and commonly platelets.

BCR-ABL

Granulocyte output

Platelet output

Slide 20 · Why those progenitors dominate remains uncertain

Preferential stimulation of granulocytic and megakaryocytic progenitors.

The molecular basis for this lineage preference is not established in the source.

Do not mistake an observed phenotype for a proven lineage-specific mechanism.

Established: Lineage bias

Uncertain: Exact cause

Slide 21 · Premature release reshapes the blood differential

Immature granulocytic cells appear in circulating blood.

They accompany, rather than replace, large numbers of mature forms.

This is a left-shifted granulocytic spectrum associated with CML.

Myelocyte

Metamyelocyte

Band

Neutrophil

Schematic cell maturation — not a blood film

Slide 22 · Marked leukocytosis is the central blood finding

Leukocytes can be strikingly increased at presentation.

Most circulating cells belong to the neutrophilic granulocytic series.

Absolute cell count alone cannot establish the genetic diagnosis.

Marked leukocytosis

Myeloid predominance

Slide 23 · A spectrum of granulocyte maturity is typical

Circulating cells include myelocytes and metamyelocytes.

Bands and segmented neutrophils are also numerous.

The co-occurrence of several maturation stages reflects preserved differentiation.

Myelocyte

Metamyelocyte

Band

Segmented

Schematic cell maturation — not a blood film

Slide 24 · Basophils and eosinophils are increased

Basophilia and eosinophilia accompany the expanded granulocytic compartment.

These components are diagnostically informative when read with the full differential.

Neither alone proves BCR::ABL positivity.

Basophils

Eosinophils

Slide 25 · Blast cells form a minority during chronic phase

In the Robbins morphology description, circulating blasts usually account for less than 10%.

Most leukocytes remain at later stages of maturation.

Rising blasts raise concern for a change in disease phase.

Chronic: Mature series dominant

Progression: Immature cells rise

Slide 26 · Thrombocytosis often accompanies leukocytosis

Platelet numbers are commonly elevated.

In some cases the platelet increase is marked.

This parallels expansion of megakaryocytic progenitors in the marrow.

Megakaryocytic drive

More platelets

Thrombocytosis

Slide 27 · Anemia contributes to the presenting symptoms

CML may have mild-to-moderate anemia.

Anemia contributes to fatigue and weakness.

The clinical picture also reflects increased metabolic demand from accelerated turnover.

Anemia

Lower oxygen delivery

Fatigue / weakness

Slide 28 · Bone marrow is markedly hypercellular

Maturing granulocytic precursors occupy much of the marrow.

The intense proliferative drive reduces the relative space available to other elements.

Hypercellularity is a tissue manifestation of the kinase-driven clone.

Illustration of increased cellularity — not histology

Slide 29 · Myeloid maturation remains evident in marrow

Granulocytic precursors occur at multiple stages.

Neutrophilic differentiation remains conspicuous.

The expanded maturing series explains the left-shifted peripheral blood picture.

Earlier precursor

Myelocyte

Band

Mature cell

Schematic cell maturation — not a blood film

Slide 30 · Erythroid progenitors are relatively preserved

Erythroid progenitors as normal or mildly decreased in number.

The dramatic feature is disproportionate granulocytic expansion.

Do not equate a lower relative erythroid proportion with complete erythroid aplasia.

Granulocytic compartment ↑

Erythroid cells ≈ / mildly ↓

Slide 31 · Megakaryocytes include small abnormal forms

Megakaryocyte numbers are increased.

Small, dysplastic megakaryocytes are a characteristic component.

This observation links tissue morphology to platelet overproduction.

Illustration of increased cellularity — not histology

Slide 32 · Sea-blue histiocytes reflect accelerated turnover

Scattered marrow macrophages may show wrinkled green-blue cytoplasm.

These are described as “sea-blue histiocytes.”

They are an associated morphologic clue, not the defining genetic lesion.

Sea-blue histiocytes

Associated marrow finding

Slide 33 · Reticulin increase is not synonymous with fibrosis

Increased reticulin deposition is typical.

Overt marrow fibrosis is uncommon in ordinary chronic-phase CML.

The two findings should not be conflated during morphologic description.

Reticulin: Often increased

Overt fibrosis: Uncommon

Slide 34 · Marrow-to-blood relationship in one view

The hypercellular marrow releases many maturing granulocytes.

The blood becomes dominated by neutrophilic forms with a left shift.

Both changes share a BCR-ABL-driven proliferative mechanism.

Marrow myeloid expansion

Early release

Blood leukocytosis

Slide 35 · Splenomegaly results from extramedullary hematopoiesis

The spleen can become massively enlarged.

Extensive hematopoietic activity develops outside the marrow.

The enlarged organ may become the most obvious clinical abnormality.

Extramedullary hematopoiesis

Schematic enlarged spleen (not a specimen)

Slide 36 · Splenic infarcts can complicate enlargement

Infarcts of varying ages are described in enlarged CML spleens.

An infarct may present with acute left upper-quadrant pain.

This differs from the chronic dragging abdominal sensation of splenomegaly.

Enlargement

Possible infarct

Schematic enlarged spleen (not a specimen)

Slide 37 · Extramedullary hematopoiesis may involve other sites

The liver may enlarge mildly.

Lymphadenopathy can accompany extramedullary hematopoiesis.

These findings are usually secondary to the systemic hematopoietic clone.

Clonal cells

Spleen

Liver / nodes

Slide 38 · CML commonly has an insidious presentation

The onset is often gradual.

Fatigue, weakness, weight loss, and anorexia may develop.

Some patients present because of splenic discomfort.

Constitutional symptoms

Abdominal manifestations

Slide 39 · Age profile: Primarily an adult disease

The peak incidence is in the fifth to sixth decades.

Children and adolescents can also be affected.

Age alone must not be used to include or exclude CML.

Adults predominate

All ages possible

Slide 40 · High cell turnover drives constitutional symptoms

Excessive hematopoietic activity is metabolically demanding.

Hypermetabolism contributes to weight loss and reduced appetite.

Fatigue and weakness reflect a combination of anemia and turnover.

Increased turnover

Hypermetabolism

Symptoms

Slide 41 · Splenic size explains characteristic discomfort

Marked splenomegaly can cause abdominal dragging or fullness.

Acute pain may indicate splenic infarction.

Symptoms should be interpreted alongside examination and blood findings.

Mass effect

Infarction pain

Schematic enlarged spleen (not a specimen)

Slide 42 · The morphologic pattern raises suspicion; Fusion proves it

Granulocytic leukocytosis, left shift, basophilia, and marrow hypercellularity suggest CML.

These findings overlap with other proliferative states.

Demonstration of BCR::ABL establishes the disease-specific molecular identity.

Suspicious blood / marrow

Molecular confirmation

CML diagnosis

Slide 43 · Chromosome analysis demonstrates the classic event

Conventional karyotyping can detect t(9;22)(q34;q11).

It documents the cytogenetic rearrangement in typical cases.

A negative routine karyotype may require further fusion testing.

Reciprocal t(9;22)

9

22

Der(9)

Der(22) / Ph

ABL

BCR

Schematic gene exchange — not a karyotype

Slide 44 · FISH can detect a cryptic fusion

Fluorescence in situ hybridization can reveal BCR::ABL despite a cryptic rearrangement.

Its role is particularly important when routine cytogenetics are non-diagnostic.

The biological target is still the BCR::ABL fusion.

Cytogenetically visible

Cryptic fusion by FISH

Slide 45 · PCR-based testing identifies the fusion sequence

PCR-based detection as an alternative to chromosome analysis.

The fusion is molecularly specific even when the chromosome event is complex.

Sensitive molecular assays also support later surveillance for recurrence.

Patient sample

PCR-based assay

BCR::ABL detected

Slide 46 · Three methods interrogate different features

Karyotype: Visible chromosomal architecture.

FISH: Physical colocalization of gene sequences.

PCR-based analysis: Fusion sequence detection.

Karyotype

Chromosome rearrangement

FISH

Fusion locus

PCR-based test

Fusion sequence

Slide 47 · CML differs molecularly from other common MPNs

CML is linked to BCR::ABL-mediated ABL signaling.

Other common MPNs often carry JAK2, CALR, or MPL pathway lesions.

The presence of BCR::ABL is therefore more discriminating than clinical overlap.

CML

BCR::ABL

Other MPNs

Often JAK2 / CALR / MPL

Slide 48 · Morphology and molecular testing are complementary

Morphology shows the tissue response and degree of maturation.

Molecular testing identifies the causal driver.

Neither clinical symptoms nor a high leukocyte count alone is sufficient for subtype assignment.

Phenotype: Morphology

Genotype: BCR::ABL

Slide 49 · Untreated CML follows a progressively unstable course

Chronic-phase disease typically progresses gradually without therapy.

Historical median survival of about 3 years without treatment.

That value must not be presented as the prognosis of modern treated CML.

Chronic phase

Possible accelerated phase

Blast crisis

Slide 50 · The accelerated phase reflects clonal evolution

About half of historically untreated patients passed through an accelerated phase.

Anemia and thrombocytopenia become more prominent.

Blood basophils may increase further.

Evolving clone

New cytopenias

Clinical acceleration

Slide 51 · Additional chromosome abnormalities accompany progression

Examples include trisomy 8.

Isochromosome 17q can emerge.

An additional copy of the Philadelphia chromosome may appear.

+8

I(17q)

Additional Ph

Slide 52 · Blast crisis resembles acute leukemia

The chronic expansion gives way to a high-grade blast population.

Progression can follow an accelerated phase or occur abruptly.

A blast crisis changes the clinical behavior of the disease dramatically.

Chronic: Maturating series

Blast crisis: Immature blasts

Slide 53 · Blast crisis need not be myeloid

Myeloid blasts in approximately 70% of crises.

Most remaining crises are of pre–B-cell lymphoid origin.

This dual potential supports a pluripotent cell of origin.

CML stem cell

Myeloid blast crisis

Lymphoid blast crisis

Slide 54 · Lymphoid transformation implicates IKZF1

Ikaros is a transcription factor encoded by IKZF1.

Alterations impairing Ikaros in most lymphoid blast crises.

The lesion connects differentiation failure with leukemic transformation.

IKZF1 / Ikaros lesion

Impaired differentiation

Lymphoid blast crisis

Slide 55 · Progression requires more than kinase activation

BCR-ABL enables persistent clone expansion.

Additional genetic events can alter differentiation and behavior.

This multistep interpretation explains the shift toward acute leukemia.

BCR-ABL founding clone

Additional abnormalities

Aggressive evolution

Slide 56 · Targeted therapy inhibits the founding kinase

BCR-ABL-directed tyrosine kinase inhibitors interrupt the driver signal.

Reduced proliferative drive controls the excess cell production.

CML is a landmark example of mechanism-based cancer treatment.

BCR-ABL activity

Kinase inhibitor

Reduced cell expansion

Slide 57 · Hematologic remission becomes common with TKIs

Sustained hematologic remissions in more than 90% of patients receiving BCR-ABL inhibitors.

Blood counts may normalize as the neoplastic output falls.

Hematologic remission does not necessarily mean every CML stem cell is eradicated.

Remission of blood counts

Residual clone may persist

Slide 58 · Inhibitors greatly reduce the risk of blast crisis

Targeted treatment lowers the number of BCR-ABL-positive cells.

It substantially decreases transition to accelerated and blast phases.

Reducing proliferation may decrease opportunities for additional oncogenic changes.

TKI exposure

Reduced clone size

Lower progression risk

Slide 59 · Leukemia stem-cell persistence limits eradication

A low-level neoplastic stem-cell reservoir can remain.

This explains why deep suppression and complete elimination are different concepts.

Sensitive molecular follow-up is relevant even in clinical remission.

CML stem-cell pool

Suppressed descendants

Potential persistence

Slide 60 · Resistance may develop through kinase alterations

In about half of resistance to first-generation agents, resistance to BCR-ABL mutations.

Other kinase alterations account for many remaining cases.

Mechanistic resistance differs from initial failure to recognize the diagnosis.

Resistance

BCR-ABL mutation

Other kinase changes

Slide 61 · Later-generation inhibitors address some resistance

Second- and third-generation agents can inhibit certain mutated BCR-ABL forms.

The choice of inhibitor depends on the resistance context.

Robbins does not specify a drug-by-mutation treatment matrix in this passage.

Resistant signaling

Alternate TKI

Re-established suppression

Slide 62 · Deep molecular remission permits selected treatment stops

Very sensitive molecular assays can monitor for recurrence.

Some patients with very deep remissions may discontinue treatment.

In a subset, remission persists for several years without ongoing therapy.

Deep remission

Careful discontinuation

Molecular surveillance

Slide 63 · Transplantation has a restricted modern role

Hematopoietic stem-cell transplantation is generally reserved for selected patients.

Otherwise healthy, relatively young patients with suboptimal TKI response.

The availability of effective kinase inhibitors altered the therapeutic landscape.

TKIs: Usual disease control

Transplant: Selected patients

Slide 64 · Clinicopathologic case: Marked leukocytosis

An adult reports several months of weakness, weight loss, and fullness in the left upper abdomen.

Blood film shows granulocytes at multiple maturation stages with basophilia.

Which molecular lesion should be sought to establish the diagnosis?

Question

BCR::ABL fusion

Slide 65 · Case analysis: Phenotype directs molecular testing

Symptoms can reflect anemia, hypermetabolism, and splenic enlargement.

Granulocytic left shift and basophilia raise CML suspicion.

A BCR::ABL-positive result supplies the defining evidence.

Clinical pattern

Blood / marrow pattern

BCR::ABL confirmation

Slide 66 · Progression case: Changing cytopenias

A patient with established CML develops worsening anemia and thrombocytopenia.

A new cytogenetic abnormality is reported and blasts increase.

The central interpretation is evolving disease phase, not simply persistent leukocytosis.

New cytopenias

Clonal progression

Slide 67 · Diagnostic synthesis

The driver lesion is BCR::ABL; The effector is constitutively active BCR-ABL kinase.

The phenotype is hypercellular granulocytic marrow and left-shifted blood leukocytosis.

The clinical threats are splenic burden, clonal evolution, and blast crisis.

Targeted kinase inhibition has transformed the expected course.

Driver

Morphology

Progression

Treatment

Slide 68 · Reference

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th edition (2026).

Primary lecture basis: Chronic Myeloid Leukemia, with the immediately preceding myeloproliferative-neoplasm context.

Diagnostic morphology here is illustrated by editable teaching schematics, not clinical photomicrographs.